Selective D1/D5 receptor antagonists for the treatment of obesity and CNS disorders

ABSTRACT

The present invention provides compounds, which, are novel antagonists for D 1 /D 5  receptors as well as methods for preparing such compounds. In another embodiment, the invention provides pharmaceutical compositions comprising such D 1 /D 5  receptor antagonists as well as methods of using them to treat CNS disorders, obesity, metabolic disorders, eating disorders such as hyperphagia, and diabetes.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No. 60/472,534 filed on May 22, 2003.

FIELD OF THE INVENTION

The present invention relates to compounds useful as D₁/D₅ receptor antagonists, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds and compositions to treat obesity, metabolic disorders and CNS disorders.

BACKGROUND OF THE INVENTION

Considerable research has been directed at controlling obesity, nicotine addiction and substance abuse. The cost to society is very high from the health costs associated with obesity and addictions. Accordingly, it would be desirable to provide a substance that would suppress cravings for food, and other substances in a predisposed patient.

Substances, which are administered to reduce craving should not produce significant physiological effects, such as stimulation of mood or elevation of blood pressure or heart rate. This could result in the substitution of one abused substance for another. Compounds that dampen the desire for the abused substance, also should not exacerbate the physiological symptoms of the abused substance in the event the individual relapses and takes the abused substance. Substances administered to reduce craving also should not produce significant adverse effects, such as dysphoria, restlessness or stiffness.

In addition to obesity and the disorders listed above, there is a strong need for drug therapy which can effectively treat, ameliorate and prevent central nervous system (CNS) disorders such as obsessive compulsive disorder, somatoform disorders, dissociative disorders, eating disorders, impulse control disorders, trichotillomania and autism. Obsessive-compulsive disorder (“OCD”), recognized to be among the most common of all psychiatric disorders, occurs in 2 to 3% of the U.S. population. OCD is characterized by anxiety-provoking and intrusive thoughts (e.g., fear of contamination and germs, doubt and uncertainty about future harm, need for symmetry, etc.), which lead to ritualistic and/or irrational behavior (e.g., constant checking, washing, touching, counting, etc.). See Hollander, et al., J. Clin. Psychiatry 57 (Suppl. 8), pp. 3-6 (1996).

Somatoform disorders (e.g., body dysmorphic disorder and hypochondriasis) are characterized by abnormal preoccupation with one's appearance or physical condition. For example, body dysmorphic disorder is a preoccupation with an imagined or slight defect in appearance. Many sufferers of body dysmorphic disorder are severely debilitated by their abnormal preoccupation, with significant impairment in social, occupational, or other important aspects of daily life. See Phillips, J. Clin. Psychiatry 57 (suppl. 8), pp. 61-64 (1996). Hypochondriasis is characterized by a persistent conviction that one is, or is likely to become ill. Many hypochondriacs are unable to work or engage in ordinary activities due to their preoccupation with illness.

Dissociative disorders (e.g., depersonalization) are characterized by sudden temporary alterations in identity, memory, or consciousness, segregating normally integrated memories or parts of the personality from the dominant identity of the individual. Depersonalization disorder, which is a dissociative disorder, is characterized by one or more episodes of depersonalization (feelings of unreality and strangeness in one's perception of the self or one's body image).

Eating disorders (e.g., anorexia nervosa, bulimia, and binge eating) are characterized by abnormal compulsions to avoid eating or uncontrollable impulses to consume abnormally large amounts of food. These disorders affect not only the social well-being, but also the physical well-being of sufferers.

Impulse control disorders (e.g., pathological gambling, compulsive buying, sexual compulsions and kleptomania) are characterized by a preoccupation with, and an inability to refrain from repeatedly engaging in various behaviors that are either socially unacceptable, or abnormally excessive by societal norms.

Trichotillomania is a habitual hair pulling that usually appears in children. See Merck Index, 15^(th) Edition (1987); Christenson, Gary; O'Sullivan, Richard, Trichotillomania: Rational treatment options, CNS Drugs (1996), 6(1), 23-34; Tukel R; Keser V; Karali N T; Olgun T O; Calikusu C., Comparison of clinical characteristics in trichotillomania and obsessive-compulsive disorder, JOURNAL OF ANXIETY DISORDERS (September-October 2001), 15(5), 433-41; du Toit P L; van Kradenburg J; Niehaus D J; Stein D J, Characteristics and phenomenology of hair-pulling: an exploration of subtypes, COMPREHENSIVE PSYCHIATRY (May-June 2001), 42(3), 247-56.

Autism is a disorder characterized by a preoccupation with one's own self and a severe impairment of the ability to perceive or react to outside stimuli in a normal fashion. Many autistics are incapable of even communicating with others.

In view of the tragic and debilitating effects of these disorders, there is a strong need for a drug therapy which can effectively treat such disorders.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides a novel class of compounds as D₁/D₅ receptor antagonists, methods of preparing such compounds, pharmaceutical compositions comprising one or more such compounds, methods of preparing pharmaceutical compositions or formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition or amelioration of obesity, metabolic disorders, CN,S disorders or one or more diseases associated with obesity using such compounds or pharmaceutical compositions.

In one aspect, the present application provides a compound, or a pharmaceutically acceptable salt or solvate of said compound, said compound having the general structure shown in formula I:

or a pharmaceutically acceptable salt or solvate of said compound, isomer or racemic mixture wherein

p is 0, 1 or 2 and when p is 0, the carbons to which (V)_(p) is shown connected are not linked to each other but are each linked to a hydrogen atom;

G is hydrogen, halogen, alkyl, alkylthio, nitro, nitrile, hydroxy, alkoxy, alkylsulfinyl, alkylsulfonyl, trifluoromethyl or trifluromethoxy;

V is —C(alkyl)₂-, —CH(alkyl)- or —CH₂—;

R¹ is hydrogen, alkyl, allyl, cycloalkyl or cycloalkyl(alkyl);

R² is one substituent selected from the group consisting of trifluoromethoxy, aryl, —NO₂, —NR⁵R⁶, —(CH₂)₁₋₆—NR⁵R⁶, —N(R⁶)C((R⁷)(R⁸))C(O)R⁸, —CN, heteroaryl, —C(O)R⁸, —C(O)OR⁸, —C(O)NR³R⁴, —S(O)₂NR³R⁴, —C(R⁷)(R⁸)NR⁵R⁶, —C(R⁷)═NOR⁴ and —C(R⁷)(R⁸)OR⁶;

R³ and R⁴ are aryl, aralkyl, alkenyl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkylalkyl, heteroaralkyl, heterocyclylalkyl, alkyl or hydrogen, or R³, R⁴ and the N to which they are attached can be joined together to form a ring selected from the group consisting of azetidine, azepane, indane, pyrrolidine, piperidine, piperazine, morpholine and

wherein said ring is unsubstituted or optionally substituted with one to four R¹⁰ moieties;

R⁵ is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heteroaralkyl, —C(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁸, —C(O)R⁸, —C(O)OR⁸or —R⁹;

R⁶ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl or heteroaryl, or R⁵, R⁶ and the N to which they are attached can be joined together to form a ring selected from the group consisting of azetidine, azepane, indane, pyrrolidine, piperidine, piperazine, morpholine and

wherein said ring is unsubstituted or optionally substituted with one to four R¹⁰ moieties;

R⁷ is hydrogen, alkyl, aryl or aralkyl;

R⁸ is hydrogen, aryl, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heteroaryl;

R⁹ is alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl or alkoxyaralkyl;

R¹⁰ is 1 to 4 substituents which can be the same or different, each R¹⁰ being independently selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkylenyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, trifluoromethyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁C(O)N—, Y₁Y₂NC(O)— and Y₁Y₂NS(O)₂—, wherein Y₁ and Y₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl or two R¹⁰ groups on adjacent carbons can be joined together to form a methylenedioxy or ethylenedioxy group;

R¹¹ is hydrogen or alkyl; and

R¹² is one to three substituents which can be the same or different, each R¹² being independently selected from the group consisting of R², halogen, alkyl, alkylthio, alkylsulfonyl, hydroxy, alkoxy and trifluoromethyl;

wherein each of said alkyl, allyl, alkylene, alkylenyl, heteroalkylene, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, aryloxyalkyl, hydroxyalkyl, alkoxyalkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, hydroxy, hydroxyalkyl, cycloalkylalkyl, heterocyclyl and cycloalkyl is unsubstituted or optionally substituted with one to four R¹⁰ moieties, where two adjacent R¹⁰ groups can be joined together to form a methylenedioxy or ethylenedioxy group.

The compounds of formula I can be useful as D₁/D₅ receptor antagonists and can be useful in the treatment of CNS disorders, metabolic disorders such as obesity and eating disorders such as hyperphagia. Another embodiment of this invention is directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula I, or a pharmaceutically acceptable salt of said compounds, and a pharmaceutically acceptable carrier therefore.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides compounds which are represented by structural formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein the various moieties are as described above.

In additional preferred embodiments of the above formula I with the structure:

wherein G, R¹, R² and R¹¹ are defined above.

Additional preferred embodiments of formula I include compounds wherein: G is halogen, R¹ is alkyl and R¹¹ is hydrogen. Compounds represented by formula I wherein G is chloro, R¹ is methyl are also preferred.

Still additional preferred embodiments of formula I include compounds wherein:

R² is —CH₂—NR⁵R⁶;

R⁵ is hydrogen;

and R⁶ is

Still additional preferred embodiments of formula I include compounds wherein:

R² is —CH₂—NR⁵ R⁶;

R⁵ is C(O)CH₃;

and R⁶ is

Still additional preferred embodiments of formula I include compounds wherein:

R² is —CH₂—NR⁵R⁶;

R⁵ is benzyl;

and R⁶ is

Still additional preferred embodiments of formula I include compounds wherein:

R² is —CH₂—NR⁵R⁶;

R⁵ is —S(O)₂-methyl;

and R⁶ is

Still additional preferred embodiments of formula I include compounds wherein:

R² is —CH₂'NR⁵R⁶;

R⁵ is —C(O)NH-ethyl;

and R⁶ is

Still additional preferred embodiments of formula I include compounds wherein:

R² is —CH₂—NR⁵R⁶;

R⁵ is —C(O)NH-isopropyl;

and R⁶ is

Still additional preferred embodiments of formula I include compounds wherein R² is selected from the group consisting of:

Still yet another class of preferred compounds of the above formula I has the structure:

wherein G, R¹, R² and R¹¹ are defined above.

In still another class of preferred compounds of formula Ib wherein: G is halogen, R¹ is alkyl and R¹¹ is hydrogen. Compounds represented by formula Ib wherein G is chloro, R¹ is methyl are also preferred.

Still yet another class of preferred compounds of formula Ib wherein R² is —NR⁵R⁶ is

R⁵ is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heteroaralkyl, —C(O)NR³R⁴, —S(O)₂R⁸ or —C(O)R⁸;

and

R⁶ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl or heteroaryl, or R⁵, R⁸ and N in —NR⁵R⁶ together can be joined together to form a ring selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, and morpholine wherein said ring is unsubstituted or optionally substituted with one or more R¹⁰ moieties.

Still yet another class of preferred compounds of formula I wherein p is 0 and R² is selected from the group consisting of:

Preferred compounds of formula I include but are not limited to Examples: 5a1, 5a14, 5a38, 5a50, 5b46, 5c16, 6a6, 6b1, 6c26, 7b7, 7c16, 7c18, 8b11, 8a3, 8c33, 13a2, 13a6, 13a7, 13a12, 13a14, 13a16, 13a19, 13a20, 13a21, 13a24, 13d1, 14t, 15l, 18a1, 18a4, 18a6, 18a8, 18b15, 19a6, 19b1, 19b5, 19b23, 19b31, 19b24, 19b32, 20a7, 20a8, 20a33, 20b5, 20b6, 20b30, 21a1, 21a2, 22a2, 22b1, 23, 24a1, 24a2, 24a3, 24b2, 25c, 27a, 29c, 30a, 34a2, 35a2 and 35a1.

The compounds of formula I can be administered as racemic mixtures or enantiomerically pure compounds.

As used above, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group, which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain, which may be straight or branched. The term “substituted alkyl” means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkylenyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, trifluoromethyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁C(O)N—, Y₁Y₂NC(O)— and Y₁Y₂NS(O)₂—, wherein Y₁ and Y₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl or two substituent groups on adjacent carbons can be joined together to form a methylenedioxy or ethylenedioxy group. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

“Alkenyl” means an aliphatic hydrocarbon group comprising at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl” means an alkenyl group having about 2 to about 6 carbon atoms in the chain, which may be straight or branched. The term “substituted alkenyl” means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkylenyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, trifluoromethyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁C(O)N—, Y₁Y₂NC(O)— and Y₁Y₂NS(O)₂—, wherein Y₁ and Y₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl or two substituent groups on adjacent carbons can be joined together to form a methylenedioxy or ethylenedioxy group. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, and n-butenyl.

“Alkylene” or “alkylenyl” means an alkanediyl group commonly having free valencies on two carbon atoms. Non-limiting examples include methylene, ethylene, propylene and the like. The term “substituted alkylene” means that the alkylene group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkylenyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, trifluoromethyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁C(O)N—, Y₁Y₂NC(O)— and Y₁Y₂NS(O)₂—, wherein Y₁ and Y₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl or two substituent groups on adjacent carbons can be joined together to form a methylenedioxy or ethylenedioxy group.

“Aryl” means an aromatic monocyclic or bicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

“Heteroaryl” means an aromatic monocyclic or bicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heteroaryls contain about 5 to about 6 ring atoms. The “heteroaryl” can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The ring system substituents can be attached to the nitrogen, oxygen and sulfur. The prefix aza, oxa or thia before the heteroaryl root name means that at least one nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like.

“Aralkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or bicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 3 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 3 to about 7 ring atoms. Included in the definition of heterocyclyl are benzo-fused cycloalkyls such as

Benzo-fused cycloalkyls can be attached to the parent moiety either through the saturated or unsaturated portions of the ring. The cycloalkyl can be optionally substituted with one or more “ring system substituents” which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable bicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkylalkyl group. Non-limiting examples of suitable cycloalkylalkyl groups include cyclopropylmethyl and cyclopropylethyl. The bond to the parent moiety is through the alkyl.

“Heterocyclyl” means a non-aromatic saturated monocyclic or bicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Included in the definition of heterocyclyl are benzo-fused heterocyclyls such as

Benzo-fused heterocyclyls can be attached to the parent moiety either through the saturated or unsaturated portions of the ring. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to 7 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted by one or more “ring system substituents” which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, pyrrolidonyl, tetrahydrothiophenyl, azepanyl and the like.

“Heterocyclylalkyl” means a heterocyclyl-alkyl group. Non-limiting examples of suitable heterocyclylalkyl groups include piperidinylmethyl and piperazinylmethyl. The bond to the parent moiety is through the alkyl.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.

“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system, which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkylenyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, trifluoromethyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁C(O)N—, Y₁Y₂NC(O)— and Y₁Y₂NS(O)₂—, wherein Y₁ and Y₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl or two substituent groups on adjacent carbons can be joined together to form a methylenedioxy or ethylenedioxy group.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

“Acyl” means an H—C(O)—, alkyl-C(O)— or cycloalkyl-C(O)—, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.

“Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the oxygen.

“Aralkoxy” means an aralkyl-O— group. Non-limiting example of a suitable aralkoxy group is benzyloxy. The bond to the parent moiety is through the oxygen.

“Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

“Heteroaralkylthio” means a heteroaralkyl-S— group in which the heteroaralkyl group is as previously described. The bond to the parent moiety is through the sulfur.

“Alkoxyalkyl” means an alkoxy-alkyl- group in which the alkoxy and alkyl groups are as previously described. The bond to the parent moiety is through the alkyl group.

“Alkoxyaryl” means an alkoxy-aryl- group in which the alkoxy and aryl groups are as previously described. The bond to the parent moiety is through the aryl group.

“Alkoxyheteroaryl” means an alkoxy-heteroaryl- group in which the alkoxy and heteroaryl groups are as previously described. The bond to the parent moiety is through the heteroaryl group.

“Alkoxyaralkyl” means an alkoxy-aralkyl- group in which the alkoxy and aralkyl groups are as previously described. The bond to the parent moiety is through the aralkyl group.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Alkoxycarbonylalkylenyl” means an alkyl-O—CO-alkylenyl group. Non-limiting examples of suitable alkoxycarbonylalkylenyl include ethoxycarbonylmethylenyl and methoxycarbonylmethylenyl. The bond to the parent moiety is through the alkylenyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. The bond to the parent moiety is through the sulfur.

“Alkylsulfinyl” means an alkyl-S(O)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moiety is through the sulfonyl.

“Heteroarylsulfonyl” means a heteroaryl-S(O₂)— group. The bond to the parent moiety is through the sulfonyl.

“Heteroarylthio” means a heteroaryl-S— group in which the heteroaryl group is as previously described. The bond to the parent moiety is through the sulfur.

The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

It should also be noted that any heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the hydrogen atom to satisfy the valences.

When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence.

As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are also contemplated herein. The term “prodrug”, as employed herein, denotes a compound that is a drug precursor which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a compound of formula I or a salt and/or solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both of which are incorporated herein by reference thereto.

“Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in antagonizing the dopamine receptor and thus producing the desired therapeutic, ameliorative or preventative effect.

The compounds of formula I can form salts, which are also within the scope of this invention. Reference to the compounds of formula I herein is understood to include reference to salts thereof, unless otherwise indicated. The term “salt(s)”, as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when compounds of formula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the formula I may be formed, for example, by reacting a compounds of formula I with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms-of the corresponding compounds for purposes of the invention.

Compounds of formula I, and salts and solvates thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts and solvates of the compounds), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate” “prodrug” and the like, is intended to equally apply to the salt, solvate and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the inventive compounds.

Compounds of formula I can have reduced potency at the Cytochrome P450 2D6 receptor and therefore can have reduced potential for affecting the metabolism of other drugs.

Compounds of formula I can be highly selective, high affinity D₁/D₅ receptor antagonists useful for the treatment of obesity.

Another aspect of this invention is a method of treating a patient (e.g., human) having a disease or condition therapeutically treated by administering a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate, of said compound to the patient.

A useful dosage is about 0.001 to 100 mg/kg of body weight/day of the compound of formula I. A preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method of treating obesity comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method for treating eating and metabolic disorders such as bulimia or anorexia comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method for treating hyperlipidemia comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method for treating cellulite and fat accumulation comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.

Another aspect of this invention is directed to a method for treating type II diabetes comprising administering to a patient a therapeutically effective amount of at least one compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound.

In addition to the “direct” effect of the compounds of this invention on the D₁/D₅ receptor, there are diseases and conditions that can benefit from weight loss such as insulin resistance, impaired glucose tolerance, Type II Diabetes, hypertension, hyperlipidemia, cardiovascular disease, gall stones, certain cancers, and sleep apnea.

The compounds of formula I are expected to be useful in the therapy of a patient suffering from obsessive compulsive disorder, a somatoform disorder, a dissociative disorder, an eating disorder, an impulse control disorder, or autism by administering an effective amount of a compound of formula I, or salt or solvate thereof.

More specifically the compounds of formula I can be useful in the treatment of a variety of eating disorders including (but not limited to) anorexia nervosa, bulimia, and binge eating.

Compounds of formula I can be useful in the treatment of a variety of impulse control disorders including (but not limited to) pathological gambling, trichotillomania, compulsive buying, and sexual compulsion.

The compounds of the invention (i.e., the compounds of formula I) may also be used in combinations with other compounds as described below. Accordingly, another aspect of this invention is a method for treating obesity comprising administering to a patient (e.g., a female or male human)

-   a. an amount of a first compound, said first compound being a     compound of the invention, a solvate thereof, or a pharmaceutically     acceptable salt of said compound or of said solvate; and -   b. an amount of a second compound, said second compound being an     anti-obesity and/or anorectic agent such as a β₃ agonist, a     thyromimetic agent, an anoretic agent, or an NPY antagonist wherein     the amounts of the first and second compounds result in a     therapeutic effect.

This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising

-   a. a first compound, said first compound being a compound of the     invention, a solvate thereof, or a pharmaceutically acceptable salt     of said compound or of said solvate; and -   b. a second compound, said second compound being an anti-obesity     and/or anorectic agent such as a β₃ agonist, a thyromimetic agent,     an anoretic, or an NPY antagonist; and/or optionally a     pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a kit comprising:

-   a. an amount of a compound of the invention, a solvate thereof, or a     pharmaceutically acceptable salt of said compound or of said solvate     and a pharmaceutically acceptable carrier, vehicle or diluent in a     first unit dosage form; -   b. an amount of an anti-obesity and/or anorectic agent such as a β₃     agonist, a thyromimetic agent, an anoretic agent, or an NPY     antagonist and a pharmaceutically acceptable carrier, vehicle or     diluent in a second unit dosage form; and -   c. means for containing said first and second dosage forms wherein     the amounts of the first and second compounds result in a     therapeutic effect.

Preferred anti-obesity and/or anorectic agents (taken singly or in any combination thereof) in the above combination methods, combination compositions and combination kits include: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as “leptin”), a leptin analog, a leptin receptor agonist, a galanin antagonist or a GI lipase inhibitor or decreaser (such as orlistat). Other anorectic agents include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine.

Another aspect of this invention is a method treating diabetes comprising administering to a patient (e.g., a female or male human)

-   a. an amount of a first compound, said first compound being a     compound of the invention, a solvate thereof, or a pharmaceutically     acceptable salt of said compound or of said solvate; and -   b. an amount of a second compound, said second compound being an     aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a     sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B     inhibitor, a dipeptidyl protease inhibitor, insulin (including     orally bioavailable insulin preparations), an insulin mimetic,     metformin, acarbose, a PPAR-gamma ligand such as troglitazone,     rosaglitazone, pioglitazone or GW-1929, a sulfonylurea, glipazide,     glyburide, or chlorpropamide wherein the amounts of the first and     second compounds result in a therapeutic effect.

This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising a first compound, said first compound being a compound of the invention, a solvate thereof, or a pharmaceutically acceptable salt of said compound or of said solvate; a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and optionally a pharmaceutical carrier, vehicle or diluent.

Another aspect of this invention is a kit comprising:

-   a. an amount of a compound of the invention, a solvate thereof, or a     pharmaceutically acceptable salt of said compound or of said solvate     and a pharmaceutically acceptable carrier, vehicle or diluent in a     first unit dosage form; -   b. an amount of an aldose reductase inhibitor, a glycogen     phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a     protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease     inhibitor, insulin (including orally bioavailable insulin     preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma     ligand such as troglitazone, rosaglitazone, pioglitazone, or     GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide and     a pharmaceutically acceptable carrier, vehicle or diluent in a     second unit dosage form; and -   c. means for containing said first and second dosage forms wherein     the amounts of the first and second compounds result in a     therapeutic effect.

For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.

For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 70 percent active ingredient. Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection.

Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

The dosage regimen utilizing the compounds of formula I or their pharmaceutical compositions of the present invention, is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter, arrest or reverse the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug. Preferably, doses of the compounds of structural formula I useful in the method of the present invention range from 0.01 to 1000 mg per adult human per day. Most preferably, dosages range from 0.1 to 500 mg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to 500 mg/kg of bodyweight. The range is more particularly from about 0.01 mg/kg to 150 mg/kg of body weight per day or most particularly 0.01 mg/kg to 10 mg/kg.

Advantageously, the active agent of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in dividend doses of two, three or four times daily.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

The following solvents and reagents may be referred to by their abbreviations in parenthesis:

-   -   Dimethylsulfoxide: DMSO     -   Butyl Lithium: BuLi     -   N-methyl pyrrolidinone: NMP     -   1-hydroxy-7-aza benzotriazole: HOAT     -   o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uranium         hexafluorophosphate: HATU     -   tetrabutyldimethylsilyl chloride: TBDMSCL     -   Reverse phase liquid chromatography mass spectroscopy: RP-LC MS     -   Triethylamine: Et₃N or TEA     -   1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride:         EDCl     -   1-hydroxybenzotriazole: HOBt     -   trifluoroacetic acid: TFA     -   acetic acid: AcOH or HOAc     -   N,N-dimethylformamide: DMF     -   Acetonitrile: CH₃CN     -   Ethanol: EtOH     -   Methanol: MeOH     -   para-toluenesulfonic acid: p-TsOH     -   Tetrahydrofuran: THF     -   1,2-dichloroethane: DCE     -   Dichloromethane: DCM     -   Di-tert-butyl dicarbonate: (Boc)₂O     -   t-butyloxycarbonyl: -Boc     -   ethyl acetate: AcOEt or EtOAc     -   Thin layer chromatography: TLC or tic     -   preparative thin layer chromatography: PTLC     -   Electrospray Mass Spectrum: ES MS     -   4-dimethylaminopyridine: DMAP     -   room temperature (ambient) about 25° C. (rt).         Experimental Procedures

Compounds 3a and 3b can be prepared analogously starting with regioisomeric bromotetralones according to Scheme 1 or alternatively by the route shown in Scheme 2 starting with the known benzazepine ecopipam. (reference: J. G. Berger, W. K. Chang, J. W. Clader, D. Hou, R. E. Chipkin, A. T. McPhail J. Med. Chem. 1989, 32, 1913-1921)

Method 1 Step 1: Process for the Compound of Formula:

Cerium trichloride (6.14 g, 0.025 moles) was stirred rapidly under vacuum and heated in an oil bath at 145-150° C. for 4 hr. Stirring was continued at 120-150° C. overnight under vacuum. The material was then stirred at r.t. An atmosphere of argon was introduced, followed by the addition of 35 mL of anhydrous THF. The suspension was stirred at room temperature for 1.5 h and was cooled to 0° C. The solution of the Grignard reagent prepared from 5-bromo-2-chloroanisole (5.25 g 0.024 moles) and magnesium turnings (0.58 g, 0.024 moles) in THF (32 mL) was added dropwise to the stirring cerium trichloride suspension at 0° C. The reaction was stirred at 0° C. for 30 min. and then overnight at room temperature. The reaction was shown to be complete by tic analysis (5% ethyl acetate/hexane). Cooling to 0° C. was followed by quenching with the dropwise addition of 50 mL of saturated aqueous ammonium chloride. The mixture was stirred at room temperature and diluted with additional sat. ammonium chloride (30 mL) and water (50 mL). The aqueous phase was extracted twice with ethyl acetate (150 mL). The combined ethyl acetate extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to a thick oil (7.01 g). The crude product was purified by column chromatography on silica gel (300 g) using 15% ethyl acetate/hexane as eluting solvent to give an oil (5.60 g). ES MS: m/z calcd for C₁₇H₁₇BrClO₂ ⁺=367.0; found m/z=367.9 (M+1)⁺

Step 2: Process for the Compound of Formula:

A solution of the above carbinol (5.50 g 0.015 moles) in toluene (150-175 mL) containing p-toluenesulfonic acid (0.010 g) was heated to reflux with the azeotropic removal of water. After 1.5 h, the reaction was cooled to room temperature. A tlc analysis (5% ethyl acetate/hexane) indicated the reaction to be complete. The toluene was evaporated under reduced pressure. The residue was partitioned between ethyl acetate (200 mL) and water (40 mL). The layers were separated and the water was extracted with ethyl acetate (125 mL). The combined ethyl acetate layers were extracted with saturated aqueous sodium bicarbonate and brine (60 mL), then dried over anhydrous sodium sulfate. The solvent was evaporated to an oil (5.28 g). Purification by column chromatography on silica gel (250 g) using 3% ethyl acetate/hexane yielded an oil (4.74 g). ES MS: m/z calcd for C₁₇H₁₅BrClO⁺=349.0; found m/z=349.1 (M+1)⁺

Step 3: Process for the Compound of Formula:

A solution of the above dihydronaphthylene (4.60 g, 0.013 moles) in acetone (45 mL) was stirred with sodium bicarbonate (4.44 g, 0.053 moles) while cooling to 0° C. A solution of Oxone (14.63 g, 0.024 moles) in water (55 mL) was added dropwise over a period 1 h. After the addition was complete, the mixture was stirred at 0° C. for 20 min. It was then warmed to room temperature. The reaction was complete after 1 hr. (tic analysis, 5% ethyl acetate/hexane). The reaction was diluted with water (75 mL) and dichloromethane (200 mL). The layers were partitioned and separated. The water was extracted with dichloromethane (400 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and evaporated to a foamy solid 4.91 g. A solution of this material in toluene (150 mis) containing ptoluenesulfonic acid (0.010 g) was heated to reflux with the azeotropic removal of water. After 2 hrs., the solution was cooled to room temperature. The toluene was evaporated under vacuum. The residue was partitioned between dichloromethane (200 mL) and saturated aqueous sodium bicarbonate (75 mL). Following the separation of the layers, the aqueous phase was extracted with dichloromethane (300 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to a foamy residue 4 67 g. ). ES MS: m/z calcd for C₁₇H₁₅BrClO₂ ⁺=365.0; found m/z=365.1 (M+1)⁺

Step 4: Process for the Compound of Formula:

A solution of the tetralone above (4.59 g, 0.013 moles) and amino acetaldehyde dimethyl acetal (1.99 g, 0.019 moles) in toluene (100 mL) was heated to reflux with the removal of water using a Dean-Stark trap. After 5 h, the solution was cooled to 0° C. The t-butyl amine-borane complex (3.29 g, 0.038 moles) was added in portions. Glacial acetic acid (3.60 mL, 0.063 moles) was added dropwise. The solution was then stirred at room temperature overnight. It was cooled in an ice bath, followed by the dropwise addition of water (10 mL) and saturated aqueous sodium bicarbonate (20 mL). The mixture was then stirred at room temperature and saturated sodium bicarbonate was added. The pH was adjusted to 9-10 with 1N sodium hydroxide. Partitioning with ethyl acetate (100 mL) and layer separation. The aqueous phase was extracted with ethyl acetate (300 mL). The combined ethyl acetate extracts were washed with brine (75 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to a semi-solid 8.89 g. This material was purified by column chromatography on silica gel (300 g). Elution with a solvent gradient 35% ethyl acetate/hexane progressing to 50% ethyl acetate/hexane. An oil (2.76 g) was obtained. ). ES MS: m/z calcd for C₂₁H₂₆BrClNO₃ ⁺=456.1; found m/z=456.1 (M+1)⁺

Step 5: Process for the Compound of Formula:

A stirring solution of the above cis amine (2.15 g, 4.73 mmol) in anhydrous DMSO (15 mL) at room temperature was treated with the addition of KOBu-t (0.150 g, 1.34 mmol) in portions. After 1h, the reaction was complete by tic. The DMSO solution was added in portions to stirring ice/saturated aqueous sodium bicarbonate (200 mL). The aqueous phase was extracted with ether (200 mL). The layers were separated and the water was extracted with ether (250 mL). The combined ether extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to a thick oil 2.03 g. This material was purified by column chromatography on silica gel (200 g) using a solvent gradient 40% ethyl acetate/hexane to 80% ethyl acetate/hexane. An oil was obtained 1.00 g. ES MS: m/z calcd for C₂₁H₂₆BrClNO₃ ⁺=456.1; found m/z=456.2 (M+1)⁺

Step 6: Process for the Compound of Formula:

A solution of the trans amine from the previous step (0.95 g, 2.09 mmol) in 5 mL of dichloromethane cooled to 0° C. was treated with the dropwise addition of methane sulfonic acid (2.0 mL, 31.4 mmol). After the addition was complete, stirring at 0° C. was continued for 15 min. and then maintained at room temperature for 2 hrs. The dichloromethane solution was added dropwise to stirring ice/water (100 mL). The aqueous mixture was made strongly basic with 3N sodium hydroxide and was extracted with dichloromethane (100 mL). The layers were separated and the water was extracted with dichloromethane (100 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to a foamy solid 0.869 g. ES MS: m/z calcd for C₂₀H₂₂BrClNO₂ ⁺=424.1; found m/z=424.1 (M+1)⁺

Step 7: Process for the Compound of Formula:

The benzazepine from step 6 above (0.40 g, 0.94 mmol) was dissolved in dichloroethane (5 mL) and cooled in an ice bath. Methane sulfonic acid (0.92 mL, 14.1 mmol) was added dropwise. After the addition was complete, stirring at 0° C. was, continued for 15 min. The reaction was then maintained at room temperature for 2 h. The reaction was then heated in an oil bath at 60 to 65° C. for 4 h. It was cooled to room temperature and the tert-butyl amine borane complex (0.41 g, 4 71 mmol) was added in portions. It was stirred at room temperature for 4 hrs. The dichloromethane solution was added to stirring ice/water (30 mL) and was made strongly basic with the addition of 3N sodium hydroxide. The mixture was extracted with dichloromethane (50 mL). The layers were separated and the water was washed with dichloromethane (100 mLs). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to a solid 0.359 g. ES MS: m/z calcd for C₁₉H₂₀BrClNO⁺=392.0; found m/z=394.1 (M+1)⁺ Step 8: Process for the Compound of Formula: 1a

To a stirring solution of the N-unsubstituted benzazepine from step 7 (0.33 g, 0.84 mmol) in DMF (2.5 mL) at room temperature was added formic acid (1.60 mL, 41.8 mmol) dropwise and 37% formaldehyde in water (4.20 mL). The reaction was heated in an oil bath at 60 to 65° C. for 3h and then at room temperature for 1.5 h. Dichloromethane (50 mL) and water (20 mL) were added followed by subsequent stirring. The aqueous phase was made strongly basic with 3N sodium hydroxide. The partitioned layers were separated and the water was extracted with dichloromethane (80 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, and evaporated to a solid 0.323 g. The product was purified by column chromatography on silica gel (30 g) eluting with a solvent gradient of 80% ethyl acetate/hexane to 95% ethyl acetate/hexane. The product was obtained as a solid 0.233 g. ES MS: m/z calcd for C₂₀H₂₂BrClNO⁺=408.1; found m/z=408.1 (M+1)⁺

Step 9: Process for the Compound of Formula: Ia

A solution of the above N-Me product from step 8 (0.030 g, 0.074 mmol) in dichloromethane (0.5 mL) was cooled to −78° C. and 1M boron tribromide in dichloromethane (0.33 mL, 0.33 mmol) was added dropwise. The reaction was stirred at −78° C. for 15 min and then maintained at room temperature for 2.5 h. Methanol (0.50 mL) was added dropwise while cooling the reaction in an ice bath. The reaction was stirred at room temperature for 45 min. and heated at reflux for 30 min. The reaction was cooled followed by stirring with water (5 mL). The reaction was made basic with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (40 mL). The layers were separated and the water was extracted with ethyl acetate (40 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, and evaporated to give 0.031 g of the phenolic benzazepine 1a as a solid. ES MS: m/z calcd for C₁₉H₂₀BrClNO⁺=394.0; found m/z=394.1 (M+1)⁺

To a suspension of 5.0 g of ecopipam (15.9 mmol) in 100 mL of dichloromethane was added 10 mL of triethylamine at room temperature under nitrogen. 4-Nitrobenzoyl chloride (3.0 g, 16.2 mmol) was added slowly and stirred at room temperature for 1 h. The reaction mixture was poured into aqueous NaHCO₃/dichloromethane mixture and extracted with 2-100 mL portions of dichloromethane. The organic extract was washed twice with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 6.8 g of 2a as a solid. ES MS: m/z calcd for C₂₆H₂₄ClN₂O₄ ⁺=463.14; found m/z=462.92 (M+1)⁺.

Compound 2b can also be made by an analogous procedure starting with a compound of formula II.

:¹HNMR (CDCl₃) δ 2.38 (m, 1H) 2.40 (s, 3H) 2.80-3.00 (m, 3H) 3.10-3.22 (m, 2H) 4.38 (d, 1H, J=8.6Hz) 6.50 (s, 1H) 7.20 (d, 2H, J=7.6Hz) 7.30 (m, 2 H) 7.39 (m, 2H) 8.18 (s, 4H).

5 g of p-nitrobenzoate, 2a, (10.8 mmol) was mixed with 10 g of neutral alumina (chromatography grade, 50-200 micron). In a separate bottle, bromine (17.27 g, 10 eq.) was mixed with 10 g of alumina. The above mixtures were shaken together for 30 minutes and charged onto a small silica gel column. The excess bromine was eluted with hexane followed by dichloromethane. The column was washed with methanol to elute the bromination products. The solvent was removed in vacuo. The resulting residue was redissolved in 50 mL of THF—H₂O (9:1) and treated with 15 mL 1N KOH. The mixture was stirred for 4h, then neutralized with acetic acid. The contents were poured into a saturated NaHCO₃/dichloromethane mixture and extracted with 2-100 mL portions of dichloromethane. The organic layer was washed with sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The products were purified by silica gel chromatography eluting with 50% acetone/hexane. The products were further purified by repeated crystallization from ethanol. This purification method gave 1.02 g of 3a: ES MS: calcd for C₁₉H₂₀BrClNO⁺=392.04, 394.04; found=394.1 (M+1)⁺as the major product.

The following compounds were also isolated by this process:

Cpd. # Structure Analytical data 3b

ES MS: calcdfor C₁₉H₂₀BrClNO⁺ =392.04, 394.04;found = 394.1(M + 1)⁺ 1a

ES MS: calcdfor C₁₉H₂₀BrClNO⁺ =392.04, 394.04;found = 394.1(M + 1)⁺

Alternatively, the aryl ring can be brominated as follows:

Step 1:

Compound 2b (0.99 g, 2.27 mmol) was dissolved in 10 mL trifluoroacetic acid followed by the addition of 0.97 g of Hg(OCOCF₃)₂. The mixture was cooled to −20° C. followed by dropwise addition of Br₂ (0.4 g, 1.1 eq). The mixture was stirred for 30 min and the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO₃. Concentration of the organic extracts gave a mixture of three products by NMR: p-Br analog 3c, o-Br analog 3d, (1:1) and a small amount of the o,p-dibromo analog, 3e. Repeated SiO₂ chromatography eluting with EtOAc:hexanes:triethylamine (50:50:1) gave 3c in 25% yield: ¹H NMR (CDCl₃) δ 2.38 (m, 1H) 2.40 (s, 3H) 2.80-3.00 (m, 3H) 3.01-3.18 (m, 2H) 4.30 (d, 1H, J=8.3 Hz) 6.50 (s, 1H) 7.05 (d, 2H, J=8.3 Hz) 7.22 (s, 1H) 7.50 (d, 2H, J=8.3 Hz) 8.18 (s, 4H).

Step 2:

Compound 3c (1.7 g, 3.29 mmol, 1 eq) was treated with NaOH (0.39 g) in 10 mL of water and 25 mL of THF under N₂. After 3 h, the pH was adjusted to 10 and extraction with dichloromethane afforded 1.2 g of phenol 3f as a white solid. ¹HNMR (CDCl₃) δ 2.38 (m, 1H) 2.40 (s, 3H) 2.70-3.10 (m, 5H) 4.20 (br, 1H, J=8.3 Hz) 5.70 (br s, 1H) 6.30 (s, 1H) 7.00 (d, 2H, J=8.3 Hz) 7.08 (s, 1H) 7.48 (d, 2H, J=8.3 Hz).

Using analogous chemistry the following compound can also be prepared

3g ¹H NMR (CDCl₃) δ 2.20 (m, 1H) 2.40 (s, 3H) 2.60-2.80 (m, 2H) 3.10 (m, 2H) 3.20-3.38 (m, 2H) 4.80 (d, 1H, J=8.8 Hz) 5.40 (br s, 1H) 6.05 (s, 1H) 7.10(s,1H) 7.10-7.38 (m, 4H) 7.60 (dd, 2H, J=1.2, 8.0Hz).

Compound 3a (2.7 g, 6.87 mmol) was dissolved in 200 mL of THF and cooled to −78° C. under nitrogen. Sodium hydride (90%, 0.25 g, 1.5 eq) was added and the mixture was stirred at −78° C. for 30 minutes. n-BuLi (2.5 M solution in hexanes, 6 mL, 2.2 eq) was added dropwise and the mixture stirred at −78° C. for 30 minutes. DMF (10 mL) was added to the above reaction mixture and the reaction stirred at −78° C. for 1 h. The reaction was quenched by the addition of saturated NH₄Cl and extracted with dichloromethane. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the product was isolated by silica gel column chromatography eluting with 3% MeOH/dichloromethane mixture to give 1.93 g of 4a as a solid. ES MS: calcd for C₂₀H₂₁ClNO₂ ⁺=342.1; found=342.1 (M+1)⁺

The following compounds can be prepared by an analogous procedure starting with regioisomeric aryl bromides:

Cpd. # Structure Analytical data 4b

ES MS: calcd forC₂₀H₂₁ClNO₂ ⁺ =342.1; found =342.1 (M + 1)⁺ 4c

The following compound can be prepared analogously from 3C:

Cpd. # Structure Analytical data 4d

ES MS: calcd forC₁₈H₁₈ClNO₂ ⁺ =315; found = (M + 1)⁺

To a preconditioned mixture of 3.70 g of 2-chlorotrityl chloride resin (0.8 mmol/g) in dichloromethane (26 mL) was added 0.985 g (2.88 mmol) of aldehyde 4a, followed by 3.2 mL (18.4 mmol) of iPr₂Net. The resulting mixture was agitated for 16 hours at ambient temperature. The reaction was quenched with 15 mL of a 10% iPr₂NEt/methanol solution and agitated for an additional 10 minutes. The liquid was drained, and the resin was washed three times each with dichloromethane, THF, and methanol. The beads were dried under reduced pressure to provide 4.40 g of resin-bound aldehyde 4a-resin.

To a 104 mg (0.62 mmol/g) of a preconditioned mixture of resin-bound 4a in 3.0 mL of dichloroethane was added 0.24 mL (2.2 mmol) of benzyl amine followed by 0.032 mL of acetic acid (0.56 mmol). The resulting mixture was agitated for 18 hours at ambient temperature. At this time, 460 mg (2.2 mmol) of Na(OAc)₃BH was added and the agitation continued for 68 hours at room temperature. The supernatant liquid was drained, and the resin was washed with methanol (3×), THF (3×), and dichloromethane (3×). The yellow beads were subjected to 3% TFA in dichloromethane (2 mL) and agitation for 25 minutes. The liquid was drained, the beads were washed with dichloromethane (3×), and the solvent was removed in vacuo. The residue was purified by preparative TLC eluting with 2M NH₃ in methanol/dichloromethane (5:95) to provide 25 mg of product 5a1 as a solid: LCMS: m/z calcd for C₂₇H₃₀ClN₂O⁺(M+1)⁺=433.2; m/z obsvd=433.1.

The following compounds can be prepared analogously:

5a

Obs. Cpd. # NR⁵R⁶ Molecular Formula Mol. Wt. (M + 1)⁺ 5a2 

C₂₅H₂₆ClN₃O 419.96 420.1 5a3 

C₂₇H₂₉ClN₂O₂ 449.00 449.1 5a4 

C₂₇H₂₈C₁₂N₂O 467.44 467.1 5a5 

C₂₆H₂₈ClN₃O 433.99 434.1 5a6 

C₂₉H₃₁ClN₂O 459.04 459.1 5a7 

C₂₈H₃₁ClN₂O₂ 463.02 463.1 5a8 

C₂₈H₂₉ClN₂O₃ 477.01 477.1 5a9 

C₂₈H₃₁ClN₂O 447.03 447.1 5a10

C₂₇H₂₈ClFN₂O 450.99 451.1 5a11

C₂₉H₃₁ClN₂O 459.04 459.1 5a12

C₂₆H₂₈ClN₃O 433.99 434.1 5a13

C₂₈H₃₁ClN₂O 447.03 447.1 5a14

C₃₃H₃₃ClN₂O 509.10 509.1 5a15

C₂₈H₂₈ClF₃N₂O 501.00 501.1 5a16

C₂₇H₂₇Cl₃N₂O 501.89 503.1 5a17

C₂₇H₂₇Cl₃N₂O 501.89 503.1 5a18

C₂₉H₃₃ClN₂O₃ 493.05 493.1 5a19

C₂₆H₂₈ClN₃O 433.99 434.1 5a20

C₃₁H₃₁ClN₂O 483.06 483.1 5a21

C₃₀H₃₅ClN₂O₃ 507.08 507.1 5a22

C₂₉H₃₁ClN₂O 459.04 459.1 5a23

C₂₈H₃₂ClN₃O 462.04 462.1 5a24

C₂₉H₃₃ClN₂O₂ 477.05 477.1 5a25

C₃₄H₃₅ClN₂O 523.12 523.1 5a26

C₂₈H₃₀Cl₂N₂O 481.47 481.1 5a27

C₂₈H₃₀Cl₂N₂O 481.47 481.1 5a28

C₂₇H₃₀ClN₃O 448.01 448.1 5a29

C₂₈H₃₀Cl₂N₂O 481.47 481.1 5a30

C₂₆H₃₃ClN₂O 425.02 425.1 5a31

C₂₅H₃₁ClN₂O₂ 426.99 427.1 5a32

C₂₅H₃₃ClN₂O 413.01 413.1 5a33

C₂₉H₃₃ClN₂O 461.05 461.1 5a34

C₃₅H₃₇ClN2O 537.15 537.1 5a35

C₂₅H₃₁ClN₂O 410.99 411.1 5a36

C₃₁H₃₅ClN₂O 487.09 487.1 5a37

C₂₄H₂₉ClN₂O 396.97 397.1 5a38

C₂₃H₂₇ClN₂O 382.94 383.1 5a39

C₂₈H₃₆ClN₃O₃ 498.07 498.1 5a40

C₃₁H₃₆ClN₃O₂ 518.10 518.1 5a41

C₂₉H₃₃ClN₄O 489.07 489.1 5a42

C₂₅H₃₂ClN₃O 426.01 426.1 5a43

C₂₈H₃₆ClN₃O₃ 498.07 498.1 5a44

C₃₁H₃₆ClN₃O 502.11 502.1 5a45

C₂₇H₃₆ClN₃O 454.06 454.1 5a46

C₂₇H₃₆ClN₃O 454.06 454.1 5a47

C₂₇H₃₆ClN₃O 454.06 454.1 5a48

C₂₆H₃₄ClN₃O₂ 456.03 456.1 5a49

C₂₈H₃₁ClN₂O 447.03 447.0 5a50

C₂₂H₂₇ClN₂O 370.93 371.1 5a51

C₂₃H₂₉ClN₂O 384.95 385.1 5a52

C₂₄H₂₉ClN₂O 396.97 397.1 5a53

C₂₆H₂₇ClN₂O 418.97 419.1 5a54

C₂₆H₂₆ClFN₂O 436.96 437.1 5a55

C₃₀H₃₃ClN₂O 473.06 473.1 5a56

C₂₆H₂₆Cl₂N₂O 453.42 453.1 5a57

C₂₆H₂₆Cl₂N₂O 453.42 453.1 5a58

C₂₆H₂₆ClFN₂O 436.96 437.1 5a59

C₂₆H₂₅Cl₃N₂O 487.86 487.1 5a60

C₃₂H₃₁ClN₂O 495.07 495.1 5a61

C₂₈H₃₀ClN₃O₃ 492.02 492.1 5a62

C₃₂H₃₃ClN₂O 497.09 497.1 5a63

C₂₈H₃₂ClN₃O 462.04 462.1 5a64

C₂₈H₃₀ClN₃O₃ 492.02 492.1 5a65

C₂₇H₃₀ClN₃O 448.01 448.1 5a66

C₂₄H₃₁ClN₂O 398.98 399.1 5a67

C₂₄H₃₁ClN₂O 398.98 399.1 5a68

C₂₄H₃₁ClN₂O 398.98 399.1 5a69

C₃₀H₃₅ClN₂O 475.08 475.1 5a70

C₂₃H₂₉ClN₂O₂ 400.95 401.1 5a71 MeNH— C₂₁H₂₅ClN₂O 356.90 357.1

The following compounds can be prepared by analogous procedures on regioisomeric starting materials:

5b

Obs. Mass Cpd. # NR⁵R⁶ Mol. Formula Mol. Wt. (M + 1)⁺ 5b1 

C₂₆H₂₇ClN₂O 418.97 419.1 5b2 

C₃₂H₃₆ClN₃O₃ 546.12 546.1 5b3 

C₃₅H₃₇ClN₂O 537.15 537.1 5b4 

C₂₄H₂₉ClN₂O 396.97 397.1 5b5 

C₂₈H₃₁ClN₂O 447.03 447.1 5b6 

C₂₅H₃₁ClN₂O 410.99 411.1 5b7 

C₂₉H₃₁ClN₂O 459.04 459.1 5b8 

C₂₉H₃₃ClN₂O₂ 477.05 477.1 5b9 

C₂₆H₃₄ClN₃O₂ 456.03 456.1 5b10

C₃₀H₄₀ClN₃O 494.13 494.1 5b11

C₃₂H₃₈ClN₃O 516.13 516.1 5b12

C₂₉H₃₃ClN₄O 489.07 489.1 5b13

C₃₁H₃₅ClN₂O 487.09 487.1 5b14

C₃₁H₃₆ClN₃O 502.11 502.1 5b15

C₂₆H₂₆Cl₂N₂O 453.42 453.1 5b16

C₂₇H₂₈Cl₂N₂O 467.44 467.1 5b17

C₂₄H₃₁ClN₂O 398.98 399.1 5b18

C₂₇H₂₉ClN₂O 433.00 433.1 5b19

C₂₆H₃₃ClN₂O 425.02 425.1 5b20

C₃₁H₃₁ClN₂O 483.06 483.1 5b21

C₂₇H₂₇ClN₂O₃ 462.98 463.1 5b22

C₃₄H₃₅ClN₂O 523.12 523.1 5b23

C₂₈H₂₉ClN₂O₃ 477.01 477.1 5b24

C₃₁H₃₆ClN₃O₂ 518.10 518.1 5b25

C₂₇H₂₈ClFN₂O 450.99 451.1 5b26

C₃₃H₃₃ClN₂O 509.10 509.1 5b27

C₂₉H₃₃ClN₂O 461.05 461.1 5b28

C₃₅H₃7ClN₂O 537.15 537.1 5b29

C₃₂H₃₃ClN₂O 497.09 497.1 5b30

C₂₉H₃₁ClN₂O 459.04 459.1 5b31

C₂₈H₃₆ClN₃O₃ 498.07 498.1 5b32

C₂₈H₃₁ClN₂O 447.03 447.1 5b33

C₃₂H₃₁ClN₂O 495.07 495.1 5b34

C₂₈H₃₂ClN₃O 462.04 462.1 5b35

C₂₈H₃₂ClN₃O 462.04 462.1 5b36

C₂₇H₃₆ClN₃O 454.06 454.1 5b37

C₃₀H₃₅ClN₂O 475.08 475.1 5b38

C₂₈H₃₀Cl₂N₂O 481.47 481.1 5b39

C₂₈H₃₀Cl₂N₂O 481.47 481.1 5b40

C₂₉H₂₈ClN₃O 470.02 470.1 5b41

C₂₇H₂₇Cl₃N₂O 501.89 503.1 5b42

C₂₇H₃₀ClN₃O 448.01 448.1 5b43

C₂₉H₃₃ClN₂O₃ 493.05 493.1 5b44

C₂₈H₃₁ClN₂O₃ 479.02 479.1 5b45

C₂₇H₃₆ClN₃O 454.06 454.1 5b46

C₂₅H₂₆ClN₃O 419.96 420.1 5b47

C₂₇H₃₈ClN₃O 456.08 456.1 5b48

C₂₈H₃₀Cl₂N₂O 481.47 481.1 5b49

C₂₆H₂₆ClFN₂O 436.96 437.1 5b50

C₂₆H₂₆Cl₂N₂O 453.42 453.1 5b51

C₂₈H₂₉ClN₂O₃ 477.01 477.1 5b52

C₂₇H₂₉ClN₂O₂ 449.00 449.1 5b53

C₂₃H₂₇ClN₂O 382.94 383.1

The following compounds can also be prepared using analogous methods:

5c

Obs. Mass Cpd. # R² Molecular Formula Mol. Wt. (M + 1)⁺ 5c1 

C₂₅H₂₇ClN₂O₂ 422.9 423 5c2 

C₃₀H₃₄ClN₃O₃ 520.1 520 5c3 

C₂₄H₂₅ClN₂O 392.9 393 5c4 

C₂₄H₂₄Cl₂N₂O 427.4 427 5c5 

C₂₇H₂₉ClN₂O 433.0 433 5c6 

C₂₅H₃₄ClN₃O 428.0 428 5c7 

C₂₅H₂₅Cl₂FN₂O 459.4 460 5c8 

C₃₃H₃₅ClN₂O 511.1 511 5c9 

C₂₃H₂₉ClN₂O 385.0 385 5c10

C₂₇H₂₉ClN₂O 433.0 433 5c11

C₂₃H₂₇ClN₂O 382.9 383 5c12

C₂₇H₃₁ClN₂O₂ 451.0 451 5c13

C₂₆H₂₈ClN₃O₃ 466.0 466 5c14

C₂₆H₃₀ClN₃O 436.0 436 5c15

C₂₄H₃₂ClN₃O 414.0 414 5c16

C₂₆H₃₅ClN₂O 427.0 427 5c17

C₂₇H₃₁ClN₂O 435.0 435 5c18

C₂₂H₂₇ClN₂O 370.9 371 5c19

C₂₇H₃₁ClN₂O 435.0 435 5c20

C₃₃H₃₅ClN₂O 511.1 511 5c21

C₂₅H₂₅ClN₂O₃ 436.9 437 5c22

C₂₇H₃₁ClN₂O 435.0 435 5c23

C₃₀H₃₅ClN₂O 475.1 475 5c24

C₃₀H₃₁ClN₂O 471.0 471 5c25

C₂₈H₃₁ClN₂O 447.0 447 5c26

C₂₇H₃₁ClN₂O 435.0 435 5c27

C₂₇H₃₁ClN₂O₃ 467.0 467 5c28

C₂₇H₂₉ClN₂O 433.0 433 5c29

C₂₇H₃₁ClN₂O₂ 451.0 451 5c30

C₂₇H₃₁ClN₂O 435.0 435 5c31

C₂₇H₃₁ClN₂O₂ 451.0 451 5c32

C₂₄H₃₁ClN₂O 399.0 399 5c33

C₂₆H₂₉ClN₂O₂ 437.0 437 5c34

C₂₆H₂₉ClN₂O 421.0 421 5c35

C₂₅H₂₅Cl₃N₂O 475.9 476 5c36

C₂₇H₃₁ClN₂O 435.0 435 5c37

C₂₁H₂₇ClN₂O₂ 374.9 375 5c38

C₂₁H₂₇ClN₂O 358.9 359 5c39

C₂₃H₂₉ClN₂O 385.0 385 5c40

C₂₂H₂₉ClN₂O 372.9 373 5c41

C₂₁H₂₇ClN₂O 358.9 359 5c42

C₂₀H₂₅ClN₂O 344.9 345

To a preconditioned mixture of 31 mg of 5a attached to resin (0.62 mmol/g) in 1.2 mL of anhydrous dichloromethane was added 0.020 mL (0.11 mmol) I—Pr₂Net, 2 mg (0.016 mmol) dimethylaminopyridine (DMAP), and 0.020 mL (0.21 mmol) of acetic anhydride. The reaction was agitated for 20 hours at ambient temperature. The liquid was drained, and the resin was washed with three times with methanol, three times with THF, and three times with dichloromethane. The product was cleaved from the solid support by treatment of the resin with 3% TFA in dichloromethane (1 mL). The liquid was drained, and the resin was washed with three times with dichloromethane. The combined filtrates were concentrated to dryness to provide 0.005 g of 6a1 as a solid: LCMS: m/z calcd for C₂₉H₃₂ClN₂O₂ ⁺ (M+1)⁺=475.2; obsvd m/z=475.3.

The following compounds can be prepared by analogous methods:

6a

Cpd. # R⁶ R⁵ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 6a2

C₃₀H₃₃ClN₂O₂ 489.1 489 6a3

C₂₉H₃₀ClFN₂O₂ 493.0 493.1 6a4

C₃₀H₃₉ClN₂O₂ 495.1 495.27 6a5

C₃₃H₃₁ClN₂O₂ 523.1 523.29 6a6

C₂₈H₂₉ClN₂O₂ 461.0 461.25 6a7

C₂₆H₃₁ClN₂O₂ 439.0 439.₂₄ 6a8

C₂₈H₃₅ClN₂O₂ 467.1 467.26 6a9

C₂₅H₃₁ClN₂O₂ 427.0 427.23 6a10

C₃₀H₃₃ClN₂O₂ 489.1 489.27 6a11

C₃₀H₃₁ClN₂O₂ 487.0 487.27 6a12

C₃4H₃₃ClN₂O₂ 537.1 537.3 6a13

C₃₃H₃₇ClN₂O₂ 529.1 529.29 6a14

C₃₀H₃₃ClN₂O₂ 489.1 489.27 6a15

C₂₇H₃₅ClN₂O₂ 455.0 455.25 6a16

C₂₈H₃₅ClN₂O₂ 467.1 467.26 6a17

C₂₇H₃₃ClN₂O₂ 453.0 453.25 6a18

C₃₁H₃₅ClN₂O₂ 503.1 503.28 6a19

C₂₅H₂₉ClN₂O₂ 425.0 425.23 6a20

C₃₁H₃₃ClN₂O₂ 501.1 501.28 6a21

C₂₆H₃₁ClN₂O₂ 439.0 439.1 6a22

C₂₈H₂₈ClFN₂O₂ 479.0 479.1

The following compounds were prepared from regioisomeric starting materials:

6b

Cpd. # R⁶ R⁵ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 6b1

C₃₄H₃₃ClN₂O₂ 537.1 537.3 6b2

C₂₇H₃₃ClN₂O₂ 453.0 453.3 6b3

C₂₉H₃₁ClN₂O₂ 475.0 475.3 6b4

C₂₈H₃₅ClN₂O₂ 467.1 467.3 6b5

C₃₀H₃₃ClN₂O₂ 489.1 489.3 6b6

C₃₀H39ClN₂O₂ 495.1 495.3 6b7

C₂₈H₂₉ClN₂O₂ 461.0 461.3 6b8

C₂6H₃₁ClN₂O₂ 439.0 439.2 6b9

C₂₅H₂₉ClN₂O₂ 425.0 425.2 6b10

C₃₁H₃₅ClN₂O₂ 503.1 503.3 6b11

C₃₀H₃₁ClN₂O₂ 487.0 487.3 6b12

C₂₈H₃₅ClN₂O₂ 467.1 467.3 6b13

C₂₅H₃₁ClN₂O₂ 427.0 427.2 6b14

C₃₃H₃₇ClN₂O₂ 529.1 529.3 6b15

C₃₃H₃₁ClN₂O₂ 523.1 523.3 6b16

C₃₁H₃₃ClN₂O₂ 501.1 501.3 6b17

C₃₀H₃₃ClN₂O₂ 489.1 489.3 6b18

C₂₇H₃₅ClN₂O₂ 455.0 455.3

The following compounds were prepared analogously from bicyclic starting materials:

6c

Cpd. # R² Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 6c1

C₃₂H₂₉ClF₂N₂O₂ 547.1 547 6c2

C₂₇H₂₉ClN₂O₂ 449.0 449 6c3

C₃₂H₃₇ClN₂O₂ 517.1 517 6c4

C₃₃H₃₀ClF₃N₂O₃ 595.1 595 6c5

C₃₀H₂₉ClN₂O₃ 501.0 501 6c6

C₂₆H₃₃ClN₂O₂ 441.0 441 6c7

C₃₁H₃₇ClN₂O₂ 505.1 505 6c8

C₃₂H₃₇ClN₂O₂ 517.1 517 6c9

C₂₃H₂₉ClN₂O₂ 401.0 401 6c10

C₂₉H₃₀ClF₃N₂O₃ 547.0 547 6c11

C₂₈H₃₀Cl₂N₂O₂ 497.5 497 6c12

C₂₉H₃₃ClN₂O₂ 477.1 477 6c13

C₂₈H₂₉ClF₂N₂O₂ 499.0 499 6c14

C₂₉H₃₃ClN₂O₃ 493.1 493 6c15

C₂₈H₃₇ClN₂O₂ 469.1 469 6c16

C₂₆H₂₉ClN₂O₃ 453.0 453 6c17

C₃₀H₃₃ClN₂O₂ 489.1 489 6c18

C₃₁H₃₄Cl₂N₂O₂ 537.5 537 6c19

C₃₁H₃₃ClF₂N₂O₂ 539.1 539 6c20

C₃₂H₃₄ClF₃N₂O₃ 587.1 587 6c21

C₃₂H₃₀Cl₂N₂O₂ 545.5 545 6c22

C₃₃H₃₃ClN₂O₂ 525.1 525 6c23

C₃₁H₄₁ClN₂O₂ 509.1 509 6c24

C₂₇H₃₇ClN₂O₂ 457.1 457 6c25

C₃₀H₄₁ClN₂O₂ 497.1 497 6c26

C₂₄H₂₉ClN₂O₂ 413.0 413 6c27

C₂₉H₃₁ClN₂O₂ 475.0 475 6c28

C₃₁H₃₅ClN₂O₂ 503 503

To a preconditioned mixture of 31 mg of 5a attached to resin (0.62 mmol/g) in 1.2 mL of anhydrous dichloromethane was added 0.017 mL (0.098 mmol) of I—Pr₂NEt followed by 0.012 mL (0.098 mmol) of benzenesulfonylchloride. The reaction was agitated for 20 hours at ambient temperature. The liquid was drained and the resin was washed with three times each with methanol, THF, and dichloromethane. The product was cleaved from the solid support by treatment of the resin with 3% TFA in dichloromethane (1 mL). The liquid was drained and the resin was washed three times with dichloromethane. The combined filtrates were concentrated to dryness to provide 0.004 g of 7a1 as a tan solid: LCMS: m/z calcd for C₃₃H₃₄ClN₂O₃S⁺ (M+1)⁺=573.2; obsvd m/z=573.3.

The following compounds can be prepared analogously:

Cpd. # R⁵ R⁶ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 7a2

C₂₅H₃₁ClN₂O₃S 475.1 475.3 7a3

C₂₉H₃₃ClN₂O₃S 525.1 525.3 7a4

C₃₀H₃₃ClN₂O₃S 537.1 537.3 7a5

C₂₉H₃₁ClN₂O₃S 523.1 523.3 7a6

C₂₄H₃₁ClN₂O₃S 463.0 463.3 7a7

C₂₄H₂9ClN₂O₃S 461.0 461.3 7a8

C₃₀H₃₃ClN₂O₃S 537.1 537.1 7a9

C₂8H₃₁ClN₂O₃S 511.1 511.3 7a10

C₂₇H₃5ClN₂O₃S 503.1 503.3 7a11

C₃₂H₃₇ClN₂O₃S 565.2 565.3

The following compounds can be prepared analogously with regioisomeric starting materials:

7b

Cpd. # R⁵ R⁶ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 7b1

C₂₅H₃₁ClN₂O₃S 475.1 475.3 7b2

C₃₃H₃₃ClN₂O₃S 573.2 573.3 7b3

C₂₄H₂9ClN₂O₃S 461.0 461.3 7b4

C₃₀H₃₃ClN₂O₃S 537.1 537.3 7b5

C₃₂H₃₇ClN₂O₃S 565.2 565.3 7b6

C₂9H₃₁ClN₂O₃S 523.1 523.3 7b7

C₂8H₃₁ClN₂O₃S 511.1 511.3 7b8

C₂₄H₃₁ClN₂O₃S 463.0 463.3 7b9

C₂₇H₃₅ClN₂O₃S 503.1 503.3 7b10

C₂9H₃₃ClN₂O₃S 525.1 525.3 7b11

C₂₇H₂9ClN₂O₃S 497.1 497.3

The following compounds can be prepared analogously with regioisomeric starting materials:

7c

Cpd. # R² Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 7c1

C₂₇H₃₁ClN₂O₃S 499.077 499 7c2

C₃₁H₃₁ClN₂O₃S 547.121 547 7c3

C₃₀H₃₅ClN₂O₃S 539.142 539 7c4

C₂₇H₃₀BrClN₂O₃S 577.973 578 7c5

C₃₁H₃₀BrClN₂O₃S 626.017 626 7c6

C₃₀H₃₄BrClN₂O₃S 618.038 618 7c7

C₃₁H₃₀ClFN₂O₃S 565.112 565 7c8

C₂₈H₃₃ClN₂O₄S 529.103 529 7c9

C₃₁H₃₄ClF₃N₂O₃S 607.14 607 7c10

C₃₀H₃₄ClFN₂O₃S 557.133 557 7c11

C₂₈H₃₀ClF₃N₂O₃S 567.075 567 7c12

C₃₁H₃₇ClN₂O₄S 569.169 69 7c13

C₂₇H₃₀ClFN₂O₃S 517.067 517 7c14

C₃₂H₃₀ClF₃N₂O₃S 615.12 615 7c15

C₃₂H₃₃ClN₂O₄S 577.148 577 7c16

C₂₃H₂₉ClN₂O₃S 449 449 7c17

C₂₈H₃₁ClN₂O₃S 511 511 7c18

C₂₅H₂₇ClN₂O₃S 471 471 7c19

C₂₀H₂₅ClN₂O₃S 409 409

To a preconditioned mixture of 31 mg of 5a attached to resin (0.62 mmol/g) in 1.1 mL of anhydrous dichloromethane (2 mL) was added 0.010 mL (0.10 mmol) of isopropyl isocyante. The reaction was agitated for 20 hours at ambient temperature. The liquid was drained, and the resin was washed three times each with methanol, THF (3×), and dichloromethane. The product was cleaved from the solid support by treatment of the resin with 3% TFA in dichloromethane (1 mL). The liquid was drained, and the resin was washed three times with dichloromethane. The combined filtrates were concentrated to dryness to provide 0.004 g of 8a1 as a tan solid: LCMS: m/z calcd for C₃₁H₃₇ClN₃O₂ ⁺ (M+1)⁺=518.25; m/z obsvd=518.30.

The following compounds can be prepared analogously:

8a

Cpd. # R⁶ R⁵ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 8a2

C₃₁H₃₆ClN₃O₂ 518.1 518.0 8a3

C₃₀H₃₃ClFN₃O₂ 522.1 522.1 8a4

C₂₈H₃₆ClN₃O₂ 482.1 482.3 8a5

C₃₁H₃₄ClN₃O₂ 516.1 516.3 8a6

C₃₃H₃₈ClN₃O₂ 544.1 544.3 8a7

C₃₀H₃₂ClN₃O₂ 502.1 502.3 8a8

C₃₀H₃₄ClN₃O₂ 504.1 504.3 8a9

C₂₇H₃₄ClN₃O₂ 468.0 468.3 8a10

C₃₃H₃₂ClN₃O₂ 538.1 538.3 8a11

C₂₇H₃₆ClN₃O₂ 470.1 470.3 8a12

C₃₄H₃₄ClN₃O₂ 552.1 552.3 8a13

C₃₀H₄₀ClN₃O₂ 510.1 510.3

The following compounds can be prepared analogously with regioisomeric starting materials:

8b

Cpd. # R⁶ R⁵ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 8b1

C₂₈H₃₆ClN₃O₂ 482.1 482.3 8b2

C₃₁H₃₄ClN₃O₂ 516.1 516.3 8b3

C₃₄H₃₄ClN₃O₂ 552.1 552.3 8b4

C₃₀H₃₂ClN₃O₂ 502.1 502.3 8b5

C₃₁H₃₆ClN₃O₂ 518.1 518.3 8b6

C₂₇H₃₄ClN₃O₂ 468.0 468.3 8b7

C₃₃H₃₈ClN₃O₂ 544.1 544.3 8b8

C₃₃H₃₂ClN₃O₂ 538.1 538.3 8b9

C₃₀H₃₄ClN₃O₂ 504.1 504.3 8b10

C₂₇H₃₆ClN₃O₂ 470.1 470.3 8b11

C₃₀H₃₄ClN₃O₂ 504.1 504.3 8b12

C₃₀H₄₀ClN₃O₂ 510.1 510.3

The following compounds can be prepared analogously with regioisomeric starting materials:

8c

Cpd. # R² Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 8c1

C₃₃H₃₄ClN₃O₂ 540.1 540 8c2

C₂₉H₃₄ClN₃O₃ 508.1 508 8c3

C₃₀H₃₆ClN₃O₂ 506.1 506 8c4

C₂₉H₃₄ClN₃O₂ 492.1 492 8c5

C₂₃H₃₀ClN₃O₂ 416.0 416 8c6

C₂₆H₃₄ClN₃O₂ 456.0 456 8c7

C₂₇H₃₀ClN₃O₂ 464.0 464 8c8

C₃₀H₃₆ClN₃O₂ 506.1 506 8c9

C₃₂H₃₈ClN₃O₃ 548.1 548 8c10

C₂₉H₃₄ClN₃O₂ 492.1 492 8c11

C₂₈H₃₂ClN₃O₂ 478.0 478 8c12

C₂₉H₃₄ClN₃O₂ 492.1 492 8c13

C₂₇H₃₆ClN₃O₂ 470.1 470 8c14

C₂₈H₃₈ClN₃O₂ 484.1 484 8c15

C₃₂H₃₈ClN₃O₂ 532.1 532 8c16

C₃₃H₄₀ClN₃O₂ 546.2 546 8c17

C₃₂H₃₈ClN₃O₂ 532.1 532 8c18

C₂₄H₃₂ClN₃O₂ 430.0 430 8c19

C₃₃H₃₄ClN₃O₃ 556.1 556 8c20

C₃₂H₃₈ClN₃O₂ 532.1 532 8c21

C₃₂H₃₈ClN₃O₂ 532.1 532 8c22

C₃₄H₃₆ClN₃O₂ 554.1 554 8c23

C₂₉H₃₄ClN₃O₂ 492.1 492 8c24

C₃₃H₃₄ClN₃O₂ 540.1 540 8c25

C₃₄H₃₆ClN₃O₂ 554.1 554 8c26

C₃₃H₃₄ClN₃O₂ 540.1 540 8c27

C₂₅H₃₄ClN₃O₂ 444.0 444 8c28

C₃₁H₄₂ClN₃O₂ 524.2 524 8c29

C₂₈H₃₈ClN₃O₂ 484.1 484 8c30

C₃₃H₄₀ClN₃O₂ 546.2 546 8c31

C₂₅H₃₂ClN₃O₂ 442.0 442 8c32

C₂₉H₃₂ClN₃O₂ 490.0 490 8c33

C₂₈H₃₂ClN₃O₂ 478 478 8c34

C₃₁H₃₆ClN₃O₂ 518 518

Compound 4a (0.025 g, 0.073 mmol) was dissolved in methanol and treated with NaBH₄ (10 mg, excess) at room temperature. The reaction mixture was stirred for 30 minutes and quenched by the addition of water. The mixture was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate. The solvent was evaporated in vacuo and the product was isolated by preparative TLC using 15% methanol in dichloromethane as eluent to give 0.019 g of 9 as a foam. ES MS: calcd for C₂₀H₂₃ClNO₂ ⁺=344.1; found=344.1 (M+1)⁺

Compound 4a (0.67 g, 1.96 mmol) was dissolved in 5 mL of pyridine and treated with hydroxylamine hydrochloride (0.2 g, 2.87 mmol). The mixture was heated at 70° C. for 4 hours. The solvent was removed in vacuo and the product was isolated by silica gel column chromatography eluting with 3-10% MeOH in dichloromethane. The oxime, 10a, was isolated in 90% yield as a solid. ES MS: m/z calcd for C₂₀H₂₂ClN₂O₂ ⁺=357.1; found m/z=357.1 (M+1)⁺.

The following compounds can be prepared by analogous methods:

Cpd. # R⁴ Analytical data 10b —CH₃ ES MS: calcd for C₂₁H₂₄ClN₂O₂ ⁺ = 371.1; found = 371.1 (M + 1)⁺ 10c —CH₂CH₃ ES MS: calcd for C₂₂H₂₆ClN₂O₂ ⁺ = 385.1; found = 385.1 (M + 1)⁺ 10d —CH₂Ph ES MS: calcd for C₂₇H₂₈ClN₂O₂ ⁺ = 447.1; found = 447.1 (M + 1)⁺ 10e —Ph ES MS: calcd for C₂₆H₂₆ClN₂O₂ ⁺ = 433.1; found = 433.1 (M + 1)⁺

The following compound could be made analogously:

Compound 3a (1.16 g, 2.95 mmol) was dissolved in 100 mL of THF and cooled to −78° C. under an atmosphere of nitrogen. Sodium hydride (65% in mineral oil, 0.2 g, 6 mmol) was added and stirred at that temperature for 30 minutes. n-BuLi (4.72 mL, 2.5M in hexanes, 4 eq) was added dropwise and stirred at −78° C. for 15 minutes. Diethylcarbonate (2 mL in 5 mL of THF) was added dropwise and the mixture was stirred for 30 minutes. The reaction was quenched by the addition of saturated aqueous NH₄Cl solution and extracted with dichloromethane. The organic layer was concentrated in vacuo and the crude ester residue used directly for the next step.

The crude ester 11 (1.0 g, 2.6 mmol) was dissolved in THF—H₂O (9:1, 100 mL) and treated with LiOH (0.5 g, 4.5 eq). The reaction mixture was heated at 70° C. for 2 hours. The solvent was removed in vacuo and the residue was redissolved in 25 mL of methanol. The mixture was neutralized with dilute aqueous hydrochloric acid. The solvent was removed in vacuo and the contents were directly charged onto a silica gel column. The product was isolated by gradient elution using 5% methanol progressing to 2N ammonia in methanol to give after concentration 0.7 g of the acid, 12, as a solid. ES MS: m/z calcd for C₂₀H₂₁ClNO₃ ⁺=358.1; found m/z=358.1 (M+1)⁺.

The following compound could be made analogously:

To a slurry of pre-swelled 2-chlorotrityl resin (2 eq, 1.0 g, 1.6 mmol/g) in 10 mL of dichloromethane was added 11 (1 eq) and diisopropylethylamine (DIEA) (8 eq). The resin was shaken overnight followed by sequential washings with 10% DIEA in methanol, dichloromethane, methanol, and THF. The resin was then dried in vacuo. Resin 11a was hydrolyzed with 0.5 N tetrabutylammonium hydroxide in THF overnight followed by sequential washings with DMF, dichloromethane, THF and methanol to give resin-bound acid 11b.

To a slurry of pre-swelled resin-bound acid 11b in NMP (0.05 g, 0.64 mmol/g) was added HATU (5 eq) and HOAT (5 eq) and the mixture was shaken for 10 min before N-methylbenzylamine (5 eq) was added. The mixture was agitated for 3 h, the solution was drained, and the resin washed with NMP followed by a recharge of the reagents. The final mixture was shaken overnight followed by sequential washing with DMF, THF, dichloromethane and methanol. The resin was cleaved with 2% TFA in dichloromethane to give 0.084 g of the desired product 13a1. RP-LC MS: m/z calcd for C₂₈H₃₀ClN₂O₂ ⁺=461.2; found m/z=461.3 (M+1)⁺.

With the same method, the following compounds can also be synthesized.

Obs. Mass Mol. (M + Cpd. # NR³R⁴ Mol. Formula Wt. 1)⁺ 13a2

C₂₉H₃₁ClN₄O₂ 503.05 504.3 13a3

C₂₉H₃₁ClN₂O₂ 475.04 476.3 13a4

C₂₆H₃₁ClN₂O₂ 439.00 440.2 13a5

C₂₅H₂₉ClN₂O₂ 424.98 426.2 13a6

C₂₅H₃₀ClN₃O₂ 439.99 441.2 13a7

C₂₈H₂₉ClN₂O₂ 461.01 462.3 13a8

C₂₅H₂₉ClN₂O₂ 424.98 426.2 13a9

C₂₄H₂₇ClN₂O₂ 410.95 412.2 13a10

C₂₆H₃₁ClN₂O₂ 439.00 439.2 13a11

C₂₃H₂₇ClN₂O₂ 398.94 400.2 13a12

C₂₂H₂₅ClN₂O₂ 384.91 386.2 13a13

C₃₁H₂₉ClN₂O₂ 497.04 497.3 13a14

C₂₆H₂₆ClN₃O₂ 447.97 448.3 13a15

C₂₈H₂₈ClFN₂O₂ 479.00 479.3 13a16

C₂₆H₂₆ClN₃O₂ 447.97 448.3 13a17

C₂₇H₂₆ClFN₂O₂ 464.97 465.3 13a18

C₂₉H₃₁ClN₂O₂ 475.04 475.3 13a19

C₂₆H₂₆ClN₃O₂ 447.97 448.3 13a20

C₂₇H₂₈ClN3O₂ 462.00 462.3 13a21

C₂₇H₂₇ClN₂O₂ 446.98 447.3 13a22

C₂₇H₂₇ClN₂O₂ 446.98 447.2 13a23

C₂₆H₂₅ClN₂O₂ 432.95 433.2 13a24

C₂₁H₂₃ClN₂O₂ 370.88 371.2

Using the same method starting with compound 32 the following compounds can also be synthesized.

Cpd. # NR³R⁴ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 13c1

C₂₅H₂₉ClN₂O₂ 424.98 425.1 13c2

C₃₀H₃₁ClN₂O₂ 487.05 487.1 13c3

C₂₇H₂₇ClN₂O₂ 446.98 447.1 13c4

C₂₅H₂₉ClN₂O₂ 424.98 425.10 13c5

C₂₈H₂₈Cl₂N₂O₂ 495.45 495.1 13c6

C₂₈H₂₈Cl₂N₂O₂ 495.45 495.1 13c7

C₃₀H₃₃ClN₂O₂ 489.06 489.1 13c8

C₃₇H₃₈ClN₃O₂ 592.19 592.1 13c9

C₂4H₂₇ClN₂O₂ 410.95 411.1 13c10

C₂₅H₂₅ClN₂O₂S 453.01 453.1 13c11

C₂4H₂₉ClN₂O₂ 412.96 413.1 13c12

C₂₅H₂₉ClN₂O₃ 440.97 441.1 13c13

C₂₉H₃₁ClN₂O₂ 475.04 475.1 13c14

C₂₈H₂₉ClN₂O₂ 461.01 461.1 13c15

C₂₃H₂₅ClN₂O₂ 396.92 397.1 13c16

C₂₈H₂₉ClN₂O₂ 461.01 461.1 13c17

C₂₇H₂₆Cl₂N₂O₂ 481.43 481.1 13c18

C₂1H₂₃ClN₂O₂ 370.88 371.1 13c19

C₂₈H₂₉ClN₂O₂ 461.01 461.1 13c20

C₂₉H₃₁ClN₂O₂ 475.04 475.1 13c21

C₂₈H₃₄ClN₃O₄ 512.05 512.1 13c22

C₂₅H₃₁ClN₂O₂ 426.99 427.1 13c23

C₂₈H₂₈ClFN₂O₂ 479.00 479.1 13c24

C₃₂H₃₆ClN₃O₂ 530.12 530.1 13c25

C₃₃H₃₅ClN₂O₃ 543.11 543.1 13c26

C₂₃H₂₇ClN₂O₂ 398.94 399.1 13c27

C₂₉H₃₁ClN₄O₂ 503.05 503.1 13c28

C₂₄H₂₇ClN₂O₃ 426.95 427.1 13c29

C₃₇H₃₇Cl₂N₃O₂ 626.63 626.2 13c30

C₃₁H₃₄ClN₃O₂ 516.09 516.1 13c31

C₂₇H₃₆ClN₃O₂ 470.06 470.1 13c32

C₂₆H₃₁ClN₂O₂ 439.00 439.1 13c33

C₂₇H₃₄ClN₃O₂ 468.04 468.1 13c34

C₂₂H₂₅ClN₂O₂ 384.91 384.9 13c35

C₂₉H₂₉ClN₂O₂ 473.02 473.1 13c36

C₂₇H₂₆ClN₃O₄ 491.98 492.1 13c37

C₂₇H₂₆ClN₃O₄ 491.98 492.1 13c38

C₃₂H₃₃ClN₄O₃ 557.10 557.1 13c39

C₂₆H₂₆ClN₃O₂ 447.97 448.1 13c40

C₂₇H₃₄ClN₃O₂ 468.04 468.1 13c41

C₃₄H₃₃ClN₂O₂ 537.11 537.1 13c42

C₂₈H₂₇ClN₂O₄ 490.99 491.1 13c43

C₂₅H₃₀ClN₃O₂ 439.99 440.1 13c44

C₂₅H₃₁ClN₂O₂ 426.99 427.1 13c45

C₂₇H₂₆ClFN₂O₂ 464.97 465.1 13c46

C₂₉H₃₁ClN₂O₂ 475.04 475.1 13c47

C₃₅H₃₅ClN₂O₂ 551.13 551.1 13c48

C₃₂H₃₁ClN₂O₂ 511.07 511.1 13c49

C₂₉H₂₉ClN₂O₂ 473.02 473.1 13c50

C₂₉H₂₉ClN₂O₂ 473.02 473.1 13c51

C₂₈H₂₉ClN₂O₂ 461.01 461.1 13c52

C₂₆H₂₆ClN₃O₂ 447.97 448.1 13c53

C₂₉H₃₁ClN₂O₂ 475.04 475.1 13c54

C₃₅H₃₅ClN₂O₂ 551.13 551.1 13c55

C₃₇H₃₆ClF₂N₃O₂ 628.17 628.2 13c56

C₂₇H₂₅Cl₂FN₂O₂ 499.42 499.1 13c57

C₂₇H₃₃ClN₂O₂ 453.03 453.1 13c58

C₂₈H₂₆ClF₃N₂O₂ 514.98 515.1 13c59

C₂5H₂₅ClN₂O₃ 436.94 437.1 13c60

C₂₇H₃₄ClN₃O₂ 468.04 468.1 13c61

C₃₃H₃₀Cl₂N₂O₂ 557.53 557.1 13c62

C₂₇H₃₃ClN₂O₂ 453.03 453.1 13c63

C₂₈H₂₆ClF₃N₂O₂ 514.98 515.1 13c64

C₂₇H₂₅Cl₃N₂O₂ 515.87 517.1 13c65

C₂₇H₂₇ClN₂O₃ 462.98 463.1 13c66

C₃₁H₂₉ClN₂O₂ 497.04 497.1 13c67

C₂₆H₃₂ClN₃O₃ 470.02 470.1 13c68

C₂₇H₂₈ClN₃O₂ 462.00 462.1 13c69

C₂₇H₂₆Cl₂N₂O₂ 481.43 481.1

Using the same method starting with compound 12b the following compounds can also be synthesized.

Cpd. # R² Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 13d1

C₂₆H₂₇ClN₂O₂ 435.0 435 13d2

C₂₅H₂₅ClN₂O₂ 420.9 421 13d3

C₂₅H₂₅ClN₂O₃ 436.9 437 13d4

C₂₆H₂₇ClN₂O₂ 435.0 435 13d5

C₂₄H₂₂Cl₂N₂O₂ 441.4 441 13d6

C₂₅H₂₅ClN₂O₂ 420.9 421 13d7

C₂₄H₂₃ClN₂O₂ 406.9 407 13d8

C₂₁H₂₅ClN₂O₃ 388.9 389 13d9

C₂₂H₂₅ClN₂O₂ 384.9 385 13d10

C₁₉H₂₁ClN₂O₂ 344.8 345 13d11

C₂₂H₂₅ClN₂O₂ 384.9 385 13d12

C₂₄H₂₉ClN₂O₂ 413.0 413 13d13

C₂₂H₂₇ClN₂O₂ 386.9 387 13d14

C₂₁H₂₅ClN₂O₂ 372.9 373 13d15

C₂₀H₂₃ClN₂O₂ 358.9 359 13d16

C₂₃H₂₇ClN₂O₂ 398.9 399 13d17

C₂₁H₂₅ClN₂O₂ 372.9 373 13d18

C₂₂H₂₅ClN₂O₃ 400.9 401 13d19

C₂₃H₂₇ClN₂O₂ 398.9 399 13d20

C₂₀H₂₃ClN₂O₂ 358.9 359

3f (1.2 g) was dissolved in 5 mL N-methylpyrrolidinone and 10 mL EtOAc followed by addition of imidazole (1.1 g, 5 eq) and t-BuMe₂SiCl (1.22 g, 2.5 eq). The mixture was stirred for 48 h. After washing with saturated NaHCO₃ and concentration, the resulting residue was purified by SiO₂ chromatography eluting with 100% dichloromethane progressing to MeOH:NH₄0H:dichloromethane=4:1:96) to provide 1.4 g the desired silylated intermediate: ¹HNMR (CDCl₃) δ 0.00 (s, 6H) 0.90 (s, 9H) 2.38 (m, 1H) 2.40 (s, 3H) 2.70-3.10 (m, 5H) 4.20 (br s, 1H) 6.10 (s, 1H) 7.05 (d, 2H, J=8.3 Hz) 7.10 (s, 1H) 7.50 (d, 2H, J=8.3 Hz).

The TBDMS ether intermediate (50 mg) was mixed with phenylboronic acid (38 mg, 3 eq), K₂CO₃ (0.1 g, 7 eq), Pd(dppf)Cl₂ (7 mg, 0.08 eq) in 1 mL DMF. The mixture was then stirred at 70° C. for 12 h. Extraction with EtOAc and washing with saturated NaHCO₃ followed by flash chromatography (100% dichloromethane to MeOH:NH₄OH:dichloromethane=4:1:96) provided 30 mg of the desired biaryl product 14a: ¹HNMR (CDCl₃) δ 2.38 (s, 3H) 2.30-2.40 (m, 1H) 2.70-2.90 (m, 3H) 3.00-3.10(m,2H) 4.22 (d, 1H, J=8.5 Hz) 6.40 (s, 1H) 7.10 (s, 1H) 7.20 (d, 2H, J=8.1 Hz) 7.35-7.60 (m, 7H).

The following products could be made using analogous techniques:

Cpd. # Ar Analytical data 14b

ES MS: calcd for C₁₉H₂₂ClN₂O₃S⁺ =393.1; found = 393.1(M + 1)⁺ 14c

ES MS: calcd for C₂₃H₂₁ClFNO⁺ =381.9; found = 382.1(M + 1)⁺ 14d

ES MS: calcd for C₂₄H₂₁ClN₂O⁺ =388.9; found = 389.1(M + 1)⁺ 14e

ES MS: calcd for C₂₄H₂₄ClNO⁺ =377.9; found = 378.1(M + 1)⁺ 14f

ES MS: calcd for C₂₄H₂₄ClNO⁺ =377.9; found = 378.1(M + 1)⁺ 14g

ES MS: calcd for C₂₄H₂₄ClNO₂ ⁺ =393.9; found = 394.1(M + 1)⁺ 14h

ES MS: calcd for C₂₁H₂₀ClNOS⁺ =369.9; found = 370.1(M + 1)⁺ 14i

ES MS: calcd for C₂₂H₂₁ClN₂O⁺ =365.9; found = 365.1(M + 1)⁺

The following products could be made using analogous techniques:

Cpd. # Ar Analytical data 14j

ES MS: calcd for C₂₅H₂₅ClNO⁺ =390; found = 390(M + 1)⁺ 14k

ES MS: calcd for C₂₆H₂₇ClNO₂ ⁺ =420; found = 420(M + 1)⁺ 14l

ES MS: calcd for C₂₇H₃₀ClN₂O⁺ =433; found = 433(M + 1)⁺ 14m

ES MS: calcd for C₂₇H₂₇ClN₂O⁺ =429; found = 429(M + 1)⁺ 14n

ES MS: calcd for C₂₅H₂₄ClFNO⁺ =408; found = 408(M + 1)⁺ 14o

ES MS: calcd forC₂₅H₂₃ClF₂NO⁺ =426; found = 426(M + 1)⁺ 14p

ES MS: calcd forC₂₆H₂₄ClF₃NO₂ ⁺ =474; found = 474(M + 1)⁺ 14q

ES MS: calcd for C₂₆H₂₇ClNO₂ ⁺ =420; found = 420(M + 1)⁺ 14r

ES MS: calcd for C₂₆H₂₄ClN₂O⁺ =415; found = 415(M + 1)⁺ 14s

ES MS: calcd for C₂₅H₂₄ClN₂O₃ ⁺ =435; found = 435(M + 1)⁺ 14t

ES MS: calcd for C₂₄H₂₄ClN₂O⁺ =391; found = 391(M + 1)⁺ 14u

ES MS: calcd for C₂₃H₂₃ClNOS⁺ =396; found = 396(M + 1)⁺

The following example illustrates the analogous procedure for N-unsubstituted analogs:

The first protection step was carried out according to Method 14: ¹HNMR (CDCl₃) δ 0.00 (s, 6H) 0.90 (s, 9H) 2.10 (m, 1H) 2.40 (s, 3H) 2.70 (m, 2H) 3.10 (m, 1H) 3.20 (m, 2H) 4.78 (d, 1H, J=8.8 Hz) 5.80 (s, 1H) 7.10 (s, 1H) 7.16-7.20 (m, 1H), 7.40 (m, 1H) 7.60 (dd, 2H, J=1.2, 8.0 Hz).

The TBS ether intermediate (1.5 g, 3.12 mmol, 1 eq) was treated with 1-chloroethyl chloroformate (1.78 g, 4 eq) in 15 mL dichloroethane at 90° C. for 3 h. The solvent was removed and 15 mL MeOH was introduced. The crude was stirred at 80° C. for 1 h. After cooling, the solvent was removed and dichloromethane was added. After washing with saturated NaHCO₃, 1.7 g of yellow solid was obtained. The solid was redissolved in 20 mL dichloromethane with Boc₂O (2.72 g, 4 eq) and Hünig's base (2.1 mL, 4 eq) and stirred for 2.5 h. After washing with saturated NaHCO₃, removal of solvent gave light brown syrup which was purified by chromatography over SiO₂ eluting with ethyl acetate:hexanes=5:95) to afford 1.4 g colorless syrup. ¹HNMR (CDCl₃) δ 0.00 (s, 6H) 0.90 (s, 9H) 1.30 (s, 9H) 2.90 (m, 1H) 3.10 (m, 1H) 3.20 (m, 1H) 3.60 (m, 1H) 3.80 (m, 1H) 4.00 (m, 1H) 4.70 (br s, 1H) 6.10 (br s, 1H) 7.10-7.40(m, 4H) 7.60 (dd, 2H, J=1.2, 8.0 Hz).

The aryl coupling reaction was carried out according to the earlier description resulting in both N-Boc and O-TBS groups cleavage. The following compounds were prepared by this method:

Cpd. # Ar Analytical data 14v

ES MS: calcd for C₂₂H₁₉ClFNO⁺ =367.9; found = 368(M + 1)⁺ 14w

ES MS: calcd for C₂₁H₁₉ClN₂O⁺ =350.9; found = 351(M + 1)⁺ 14x

ES MS: calcd for C₂₃H₂₂ClNO⁺ =363.9; found = 364(M + 1)⁺ 14y

ES MS: calcd for C₂₃H₂₂ClNO⁺ =363.9; found = 364(M + 1)⁺ 14z

ES MS: calcd for C₂₃H₂₂ClNO₂ ⁺ =379.9; found = 380(M + 1)⁺ 14aa

ES MS: calcd for C₂₀H₁₈ClNOS⁺ =355.9; found = 356(M + 1)⁺

Compound 2a (0.1 g, 0.216 mmol) was dissolved in 2 mL of dichloromethane and cooled to 0° C. under nitrogen. Chlorosulfonic acid (neat, 1 mL, excess) was added dropwise over 10 minutes and stirred at 0° C. for 3 hours. The solvent was removed in vacuo to obtain an oil. The oil was redissolved in 2 mL of THF and treated with 1 mL of aqueous dimethylamine (40% solution) and stirred at room temperature overnight. The solvent was removed in vacuo and the product was purified by preparative TLC using 10% methanol in dichloromethane as eluent to give 0.048 g of 15a as a solid. ES MS: calcd for C₂₁H₂₆ClN₂O₃S⁺=421.1; found=421.1 (M+1)⁺.

The following compounds can be prepared by analogous chemistry:

15

Cpd. # NR³R⁴ Analytical data 15b —NH₂ ES MS: calcd for C₁₉H₂₂ClN₂O₃S⁺ = 393.1; found = 393.1(M + 1)⁺ 15c —NHMe ES MS: calcd for C₂₀H₂₄ClN₂O₃S⁺ = 407.1; found = 407.1(M + 1)⁺ 15d

ES MS: calcd forC₂₃H₂₈ClN₂O₃S⁺ =447.1; found = 447.1(M + 1)⁺ 15e

ES MS: calcd forC₂₄H₃₀ClN₂O₃S⁺ =462.1; found = 462.1(M + 1)⁺ 15f

ES MS: calcd forC₂₄H₃₁ClN₃O₃S⁺ =477.1; found = 477.1(M + 1)⁺ 15g

ES MS: calcd forC₂₃H₂₈ClN₂O₄S⁺ =463.1; found = 463.1(M + 1)⁺ 15h

ES MS: calcd forC₂₅H₂₆ClN₂O₃S⁺ =470.1; found = 470.1(M + 1)⁺ 15i

ES MS: calcd forC₂₆H₂₈ClN₂O₃S⁺ =484.1; found = 484.1(M + 1)⁺ 15j

ES MS: calcd forC₂₆H₂₈Cl₂N₂O₃S⁺ =504.1; found = 504.1(M + 1)⁺ 15k

ES MS: calcd forC₂₆H₂₈ClN₂O₄S⁺ =500.1; found = 500.1(M + 1)⁺ 15l

ES MS: calcd forC₂₆H₂₈ClN₂O₃S⁺ =484.1; found = 484.1(M + 1)⁺ 15m

ES MS: calcd forC₂₇H₃₀ClN₂O₃S⁺ =498.1; found = 498.1(M + 1)⁺ 15n

ES MS: calcd forC₂₆H₂₇BrClN₂O₃S⁺ =562.1; found =562.1(M + 1)⁺ 15o

ES MS: calcd forC₂₄H₂₆ClN₂O₄S⁺ =473.1; found = 473.1(M + 1)⁺ 15p

ES MS:calcd for C₂₄H₂₆ClN₂O₃S₂ ⁺ =490.1; found = 490.1(M + 1)⁺

Compound 2a (2.0 g, 4.32 mmol) was dissolved in 30 mL of acetonitrile, treated with BF₄NO₂ (1.6 g, 3 eq) at room temperature and stirred for 3 hours. The reaction was quenched by the addition of water and neutralized with saturated aqueous NaHCO₃ solution. The mixture was extracted with dichloromethane and dried over sodium sulfate. The solvent was removed in vacuo and the crude material was used as such for the next step. The crude mixture was redissolved in 40 mL of THF:H₂O (3:1,) and treated with LiOH (1 g in 40 mL water) and stirred at room temperature for 3 hours. The reaction mixture was neutralized with acetic acid and extracted with dichloromethane. The solvent was removed in vacuo and passed through a short pad of silica gel to remove the base line material. The products were isolated by HPLC using a silica gel column and eluting with 95% ethyl acetate/hexane containing 0.25% triethylamine.

16a (C10 isomer): 0.15 g, 10%. ES MS: m/z calcd for C₁₉H₂₀ClN₂O₃ ⁺=359.1; found m/z=359.1 (M+1)⁺

16b (C11 isomer): 0.22 g, 14%. ES MS: m/z calcd for C₁₉H₂₀ClN₂O₃ ⁺=359.1; found m/z=359.1 (M+1)⁺

16c (C12 isomer): 0.50 g, 32%. ES MS: m/z calcd for C₁₉H₂₀ClN₂O₃ ⁺=359.1; found m/z=359.1 (M+1)⁺

Compound 16c (0.05 g, 0.139 mmol) was dissolved in 10 mL of ethanol and 0.04 g of SnCl₂.2H₂O (0.156 mmol) was added. Acetic acid (3 drops) was added and the resulting mixture was heated under reflux for 2 hours. Water was added and the mixture was extracted with dichloromethane. The extract was dried over sodium sulfate and evaporated in vacuo. The product was isolated by preparative TLC using 5% MeOH in dichloromethane as eluent to give 0.03 g of aniline 17c. ES MS: m/z calcd for C₁₉H₂₂ClN₂O⁺=329.1; found m/z=329.1 (M+1)⁺.

To a cartridge containing 1.84 g of Wang resin (1.0 mmol/g, 1 eq) pre-swelled in THF was added nitro compound 16b (1 eq) and triphenylphospine (2 eq) in 20 ml of THF followed by the addition of azodicarbonyldipiperidine (2 eq) in 10 ml of dichloromethane. After the mixture was agitated overnight, acetic acid (2 eq) was added and the final mixture was shaken for 2 more hours. The resin was sequentially washed with dichloromethane, THF and methanol, and dried in vacuo to give resin-bound 16d.

To the resin 16d suspended in DMF was added diisopropylethylamine (6 eq) and SnCl₂.2H₂O (20 eq) under nitrogen. The mixture was agitated overnight followed by sequential washing with H₂O, EDTA (0.05M), DMF, dichloromethane, THF, and methanol. The product was cleaved from the resin (0.043 g) using 30% trifluoroacetic acid in dichloromethane to give 0.01 g of aniline 17b. ES MS: m/z calcd for C₁₉H₂₂ClN₂O⁺=329.1; found m/z=329.1 (M+1)⁺.

The C10 aniline isomer 17a can also be prepared by this method starting with nitro derivative 16a: 17a (C12 isomer): ES MS: m/z calcd for C₁₉H₂₂ClN₂O⁺=329.1; found m/z=329.1 (M+1)⁺.

To 0.03 g of the resin-bound amine 17 (0.69 mmol/g) pre-swelled in DMF was added a solution of cyclopropane carboxylic acid (5 eq), HOBT (5 eq) and EDCl (5 eq) in DMF. The mixture was agitated overnight and the resin washed with DMF, THF, dichloromethane and methanol. Cleavage with 30% trifluoroacetic acid in dichloromethane and formation of the HCl salt generated 0.0102 g of compound 18a1: RP-LC MS: m/z calcd for C₂₃H₂₆ClN₂O₂ ⁺=397.1; found m/z=397.1 (M+1)⁺.

The following compounds can be synthesized by the same method:

wherein R⁶ is hydrogen:

Mol. Obs. Mass Cpd. # R⁵ Mol. Formula Wt. (M + 1)⁺ 18a2

C₂₄H₂₃ClN₂O₂S 438.98 439.1 18a3

C₂₄H₂₃ClN₂O₃ 422.92 423.1 18a4

C₂1H₂₃ClN₂O₂ 370.88 371.1 18a5

C₂₇H₃₃ClN₂O₂ 453.03 453.1 18a6

C₂₅H₂₉ClN₂O₂ 424.98 425.1 18a7

C₂₄H₂₉ClN₂O₂ 412.96 413.1 18a8

C₂₄H₂₇ClN₂O₂ 410.95 411.1 18a9

C₂₄H₂₇ClN₂O₃ 426.95 427.1 18a10

C₂₇H₂₇ClN₂O₂ 446.98 447.1 18a11

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18a12

C₂₆H₂₅ClN₂O₂ 432.95 433.1 18a13

C₂₇H₂₇ClN₂O₃ 462.98 463.1 18a14

C₂₇H₂₇ClN₂O₃ 462.98 463.1 18a15

C₃₀H₂₇ClN₂O₂ 483.02 483.1 18a16

C₂₇H₂₇ClN₂O₂ 446.98 447.1 18a17

C₂₆H₂₃Cl₃N₂O₂ 501.84 503.1 18a18

C₂₆H₂₄Cl₂N₂O₂ 467.40 467.1 18a19

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18a20

C₃₀H₂₇ClN₂O₂ 483.02 483.1 18a21

C₂₇H₂₄ClF₃N₂O₂ 500.95 501.1 18a22

C₂₄H₂₄ClN₃O₃ 437.93 438.1 18a23

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18a24

C₃₂H₂₉ClN₂O₂ 509.05 509.1

The following compounds can also be prepared using this method starting with the regioisomeric resin bound amines 17:

wherein R⁶ is hydrogen:

Obs. Mass (M + Cpd. # R⁵ Mol. Formula Mol. Wt. 1)⁺ 18b1 

C₂₆H₂₃Cl₃N₂O₂ 501.84 502.1 18b2 

C₂₄H₂₃ClN₂O₂S 438.98 439.1 18b3 

C₂₄H₂₃ClN₂O₃ 422.92 423.1 18b4 

C₂1H₂₃ClN₂O₂ 370.88 371.1 18b5 

C₂₇H₃₃ClN₂O₂ 453.03 453.1 18b6 

C₂₃H₂₅ClN₂O₂ 396.92 397.1 18b7 

C₂₅H₂₉ClN₂O₂ 424.98 425.1 18b8 

C₂₄H₂₇ClN₂O₂ 410.95 411.1 18b9 

C₂₄H₂₇ClN₂O₃ 426.95 427.1 18b10

C₂₇H₂₇ClN₂O₂ 446.98 447.1 18b11

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18b12

C₂₄H₂₉ClN₂O₂ 412.96 413.1 18b13

C₂₆H₂₅ClN₂O₂ 432.95 433.1 18b14

C₂₇H₂₇ClN₂O₃ 462.98 463.1 18b15

C₃₀H₂₇ClN₂O₂ 483.02 483.1 18b16

C₂₇H₂₇ClN₂O₂ 446.98 447.1 18b17

C₂₆H₂₄Cl₂N₂O₂ 467.40 468.1 18b18

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18b19

C₃₀H₂₇ClN₂O₂ 483.02 483.1 18b20

C₂₇H₂₄ClF₃N₂O₂ 500.95 501.1 18b21

C₂₄H₂₄ClN₃O₃ 437.93 438.1 18b22

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18b23

C₃₂H₂₉ClN₂O₂ 509.05 509.1 18b24

C₂₇H₂₇ClN₂O₃ 462.98 463.1

The following compounds can also be prepared using this method starting with the regioisomeric resin bound amine 17:

wherein R⁶ is hydrogen:

Obs. Mass Cpd. # R⁵ Mol. Formula Mol. Wt. (M + 1)⁺ 18c1 

C₂₆H₂₅ClN₂O₂ 432.95 433.1 18c2 

C₂₆H₂₄ClN₃O₄ 477.95 478.1 18c3 

C₂8H₂₃ClF₆N₂O₂ 568.95 569.1 18c4 

C₂₇H₂₇ClN₂O₃ 462.98 463.1 18c5 

C₂₇H₂₇ClN₂O₃ 462.98 463.1 18c6 

C₂₇H₂₄ClF₃N₂O₂ 500.95 501.1 18c7 

C₃₀H₂₇ClN₂O₂ 483.02 483.1 18c8 

C₂₇H₂₇ClN₂O₂ 446.98 447.1 18c9 

C₂₆H₂₃Cl₃N₂O₂ 501.84 503.1 18c10

C₂₄H₂₃ClN₂O₂S 438.98 439.1 18c11

C₂₆H₂₄Cl₂N₂O₂ 467.40 467.1 18c12

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18c13

C₃₀H₂₇ClN₂O₂ 483.02 483.1 18c14

C₂₇H₂₄ClF₃N₂O₂ 500.95 501.1 18c15

C₂₉H₃₁ClN₂O₅ 523.03 523.1 18c16

C₂₄H₂₄ClN₃O₃ 437.93 438.1 18c17

C₂₇H₂₃ClF₄N₂O₂ 518.94 519.1 18c18

C₂₅H₂₄ClN₃O₂ 433.94 434.1 18c19

C₂₆H₂₃ClF₃N₃O₂ 501.94 502.1 18c20

C₃₂H₂₉ClN₂O₂ 509.05 509.1 18c21

C₂₄H₂₃ClN₂O₃ 422.92 423.1 18c22

C₂1H₂₃ClN₂O₂ 370.88 371.1 18c23

C₂8H₃₀ClN₃O₂ 476.02 476.1 18c24

C₂8H₃₅ClN₂O₂ 467.06 467.1 18c25

C₂₆H₂₃Cl₂FN₂O₂ 485.39 485.1 18c26

C₂₉H₂₆ClN₃O₂ 484.00 484.1 18c27

C₂₄H₂₃ClN₄O₂ 434.93 435.1 18c28

C₂₉H₂₉ClN₂O₂ 473.02 473.1 18c29

C₂₇H₂₄ClN₃O₂ 457.96 458.1 18c30

C₂8H₂₇ClN₂O₄ 490.99 491.1 18c31

C₂₉H₂₉ClN₂O₃ 489.02 489.1 18c32

C₃₀H₂₉ClN₂O₂S 517.10 517.1 18c33

C₂₅H₂₅ClN₄O₂ 448.96 449.1 18c34

C₂₉H₃₁ClN₂O₂ 475.04 475.1 18c35

C₂₂H₂₅ClN₂O₃ 400.91 401.1 18c36

C₂₃H₂₇ClN₂O₂ 398.94 399.1 18c37

C₂₇H₂₇ClN₂O₂ 446.98 447.1 18c38

C₃₁H₂₉ClN₂O₂ 497.04 497.1 Method 19

The following compounds can be synthesized using similar chemistry starting with the regioisomeric resin-bound aniline 17.

wherein R⁶ is hydrogen:

Obs. Mass Cpd. # R⁵ Mol. Formula Mol. Wt. (M + 1)⁺ 19a1 

C₂0H₂₃ClN₂O₃S 406.9 408.1 19a2 

C₂₆H₂₇ClN₂O₃S 483.0 484.1 19a3 

C₂₄H₂₆ClN₃O₄S 488.0 489.1 19a4 

C₂₅H₂₅ClN₂O₃S 469.0 470.1 19a5 

C₂1H₂₅ClN₂O₃S 421.0 422.1 19a6 

C₂₅H₂₄ClFN₂O₃S 487.0 488.1 19a7 

C₂₆H₂₇ClN₂O₃S 483.0 484.1 19a8 

C₂₇H₂8ClN₃O₄S 526.1 436.1 19a9 

C₂₅H₂₄Cl₂N₂O₃S 503.5 505.1 19a10

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19a11

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19a12

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19a13

C₂₆H₂₇ClN₂O₄S 499.0 500.1 19a14

C₂₉H₂₇ClN₂O₃S 519.1 520.1 19a15

C₃₁H₃₁ClN₂O₃S 547.1 548.1 19a16

C₂₃H₂₅ClN₄O₃S 473.0 474.1 19a17

C₂₄H₂₆Cl₂N₄O₃S 521.5 523.1 19a18

C₂₂H₂₇ClN₂O₃S 435.0 435.1 19a19

C₂₂H₂₇ClN₂O₃S 435.0 436.1 19a20

C₂₆H₂₇ClN₂O₃S 483.0 484.1 19a21

C₂₃H₂₂Cl₂N₂O₃S₂ 509.5 511.1 19a22

C₂₆H₂₄ClN₃O₃S 494.0 495.1 19a23

C₂₅H₂₄Cl₂N₂O₃S 503.5 505.1 19a24

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19a25

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19a26

C₂₅H₂₄ClFN₂O₃S 487.0 488.1 19a27

C₂₉H₂₇ClN₂O₃S 519.1 520.1 19a28

C₂₆H₂₄ClF₃N₂O₃S 537.0 538.1 19a29

C₂₆H₂₄ClF₃N₂O₃S 537.0 538.1 19a30

C₂₅H₂₃ClN₄O₄S 511.0 512.1 19a31

C₂₃H₂₃ClN₂O₃S₂ 475.0 476.1 19a32

C₂₁H₂₆ClN₃O₃S 436   436.1

17

19b

19b1

To 0.03 g of the resin-bound aniline 17 (0.69 mmol/g) pre-swelled in pyridine was added 5 eq of methanesulfonylchloride. The mixture was agitated overnight and the resin 19b was washed with DMF, THF, dichloromethane and methanol. The product was cleaved from the resin with 30% TFA in dichloromethane to give compound 19b1. RP-LC MS: m/z calcd for C₂₀H₂₄ClN₂₀O₃S⁺=407.1; found m/z=407.1 (M+1)⁺.

The following compounds can be synthesized using related chemistry.

wherein R⁶ is hydrogen:

Obs. Mass Cpd. # R⁵ Mol. Formula Mol. Wt. (M + 1)⁺ 19b2 

C₂₅H₂₅ClN₂O₃S 469.0 469.1 19b3 

C₂₆H₂₇ClN₂O₃S 483.0 483.1 19b4 

C₂₄H₂₆ClN₃O₄S 488.0 488.1 19b5 

C₂1H₂₅ClN₂O₃S 421.0 421.1 19b6 

C₂₅H₂₄ClFN₂O₃S 487.0 487.1 19b7 

C₂₆H₂₇ClN₂O₃S 483.0 483.1 19b8 

C₂₇H₂₈ClN₃O₄S 526.1 526.1 19b9 

C₂₅H₂₄Cl₂N₂O₃S 503.5 503.1 19b10

C₂₃H₂₂Cl₂N₂O₃S₂ 509.5 509.1 19b11

C₂₅H₂₄Cl₂N₂O₃S 503.5 503.1 19b12

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19b13

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19b14

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19b15

C₂₅H₂₃Cl₃N₂O₃S 537.9 539.1 19b16

C₂₅H₂₄ClFN₂O₃S 487.0 487.1 19b17

C₂₆H₂₇ClN₂O₄S 499.0 499.1 19b18

C₂₉H₂₇ClN₂O₃S 519.1 519.1 19b19

C₂₉H₂₇ClN₂O₃S 519.1 519.1 19b20

C₃₁H₃₁ClN₂O₃S 547.1 547.1 19b21

C₂₃H₂₅ClN₄O₃S 473.0 473.0 19b22

C₂₄H₂₆Cl₂N₄O₃S 521.5 521.5 19b23

C₂₂H₂₇ClN₂O₃S 435.0 435.0 19b24

C₂₆H₂₄ClN₃O₃S 494.0 494.0 19b25

C₂₅H₂₃Cl₃N₂O₃S 537.9 537.9 19b26

C₂₅H₂₃Cl₃N₂O₃S 537.9 537.9 19b27

C₂₆H₂₄ClF₃N₂O₃S 537.0 537.0 19b28

C₂₆H₂₄ClF₃N₂O₃S 537.0 537.0 19b29

C₂₅H₂₃ClN₄O₄S 511.0 511.0 19b30

C₂₃H₂₃ClN₂O₃S₂ 475.0 475.0 19b31

C₂₆H₂₇ClN₂O₃S 483.0 483.0 19b32

C₂₁H₂₆ClN₃O₃S 436   436.1 Method 20

The following compounds can be synthesized using similar methodology starting with the regioisomeric resin-bound aniline 17.

wherein R⁶ is hydrogen and R⁵is C(O)NR³R⁴:

Obs. Mass Mol. (M + Cpd. # NR³R⁴ Mol. Formula Wt. 1)⁺ 20a1 

C₂₆H₂₅Cl₂N₃O₂ 482.4 484.1 20a2 

C₂₇H₂₈ClN₃O₂ 462.0 463.1 20a3 

C₂₆H₂₅Cl₂N₃O₂ 482.4 484.1 20a4 

C₂₆H₂₅Cl₂N₃O₂ 482.4 484.1 20a5 

C₂₂H₂₆ClN₃O₂ 399.9 401.1 20a6 

C₂₄H₂₈ClN₃O₃ 442.0 443.1 20a7 

C₂₄H₂₈ClN₃O₂ 426.0 427.1 20a8 

C₂₂H₂₆ClN₃O₂ 399.9 401.1 20a9 

C₂₆H₃₂ClN₃O₂ 454.0 455.1 20a10

C₂₇H₂₈ClN₃O₃ 478.0 479.3 20a11

C₂₇H₂₈ClN₃O₃ 478.0 479.3 20a12

C₂₇H₂₅ClN₄O₂ 473.0 474.3 20a13

C₂₇H₂₅ClN₄O₂ 473.0 474.3 20a14

C₂₆H₂₅ClFN₃O₂ 466.0 467.3 20a15

C₂₆H₂₅ClFN₃O₂ 466.0 467.3 20a16

C₂₆H₂₅ClFN₃O₂ 466.0 467.3 20a17

C₂₈H₂₈ClN₃O₃ 490.0 491.3 20a18

C₂₆H₂₄Cl₃N₃O₂ 516.9 518.3 20a19

C₂₆H₂₄Cl₃N₃O₂ 516.9 518.3 20a20

C₂₆H₂₄Cl₃N₃O₂ 516.9 518.3 20a21

C₂₇H₂₆Cl₃N₃O₂ 530.9 532.3 20a22

C₃₀H₂₈ClN₃O₂ 498.0 499.3 20a23

C₂₇H₂₅ClF₃N₃O₂ 516.0 517.3 20a24

C₂₇H₂₅ClF₃N₃O₂ 516.0 517.3 20a25

C₂₆H₂₆ClN₃O₂ 448.0 449.3 20a26

C₂₈H₃₁ClN₄O₂ 491.0 492.3 20a27

C₂₄H₃₀ClN₃O₂ 428.0 428.2 20a28

C₂₅H₃₀ClN₃O₂ 440.0 440.2 20a29

C₂₇H₂₈ClN₃O₃ 478.0 478.3 20a30

C₃₃H₃₂ClN₃O₂ 538.1 538.3 20a31

C₂₈H₃₀ClN₃O₂ 476.0 476.3 20a32

C₂₃H₂₈ClN₃O₂ 414.0 414.2 20a33

C₂₅H₂₃Cl₃N₄O₂ 517.8 518.3

17

20b1

To 0.03 g of the resin-bound aniline 17 (0.69 mmol/g) pre-swelled in pyridine was added a solution of N,N′-dimethylaminocarbonylchloride (5 eq). The mixture was agitated overnight and the resin was washed with DMF, THF, dichloromethane and methanol. The product was cleaved from the resin with 30% TFA in dichloromethane to give compound 20b1. RP-LC MS: m/z calcd for C₂₂H₂₇ClN₃O₂ ⁺=400.1; found m/z=400.1 (M+1)⁺.

The following compounds can be synthesized using similar methodology.

wherein R⁶ is hydrogen and R⁵ is C(O)NR³R⁴:

Obs. Mass Mol. (M + Cpd. # NR³R⁴ Mol. Formula Wt. 1)⁺ 20b2 

C₂₆H₂₅Cl₂N₃O₂ 482.4 482.1 20b3 

C₂₇H₂₈ClN₃O₂ 462.0 462.1 20b4 

C₂₆H₂₅Cl₂N₃O₂ 482.4 482.1 20b5 

C₂₆H₂₅Cl₂N₃O₂ 482.4 482.1 20b6 

C₂₂H₂₆ClN₃O₂ 399.9 399.9 20b7 

C₂₄H₂₈ClN₃O₃ 442.0 442.0 20b8 

C₂₄H₂₈ClN₃O₂ 426.0 426.0 20b9 

C₂₇H₂₈ClN₃O₂ 462.0 462.0 20b10

C₂₆H₃₂ClN₃O₂ 454.0 454.0 20b11

C₂₇H₂₈ClN₃O₃ 478.0 478.3 20b12

C₂₇H₂₈ClN₃O₃ 478.0 478.3 20b13

C₂₇H₂₈ClN₃O₃ 478.0 478.3 20b14

C₂₇H₂₅ClN₄O₂ 473.0 473.3 20b15

C₂₇H₂₅ClN₄O₂ 473.0 473.3 20b16

C₂₆H₂₅ClFN₃O₂ 466.0 466.3 20b17

C₂₆H₂₅ClFN₃O₂ 466.0 466.3 20b18

C₂₆H₂₅ClFN₃O₂ 466.0 466.3 20b19

C₂₈H₂₈ClN₃O₃ 490.0 490.3 20b20

C₂₆H₂₄Cl₃N₃O₂ 516.9 517.3 20b21

C₂₆H₂₄Cl₃N₃O₂ 516.9 517.3 20b22

C₂₇H₂₆Cl₃N₃O₂ 530.9 531.3 20b23

C₃0H₂₈ClN₃O₂ 498.0 498.3 20b24

C₂₇H₂₅ClF₃N₃O₂ 516.0 516.3 20b25

C₂₆H₂₆ClN₃O₂ 448.0 448.3 20b26

C₂₈H₃₁ClN₄O₂ 491.0 491.3 20b27

C₂₄H₃0ClN₃O₂ 428.0 428.2 20b28

C₂₅H₃0ClN₃O₂ 440.0 440.2 20b29

C₃₃H₃₂ClN₃O₂ 538.1 538.3 20b30

C₂₆H₂₄Cl₃N₃O₂ 516.9 517.3 20b31

C₃₈H₃0ClN₃O₂ 476.0 476.23 20b32

C₂₇H₂₅ClF₃N₃O₂ 516.0 516.3 20b33

C₂₃H₂₈ClN₃O₂ 414.0 414.2 20b34

C₂₅H₂₃Cl₃N₄O₂ 517.8 518.3

To 0.100 g of pre-swelled resin 18 (0.69 mmol/g) was added 4 mL of 2N BH₃ in THF and the mixture was agitated overnight. The resin was sequentially washed with methanol, 0.5 M NaOMe in methanol, dichloromethane, THF, and methanol. The product was cleaved from 0.050 g of the resin with 30% TFA in dichloromethane to give compound 21a1. RP-LC MS: m/z calcd for C₂₆H₂₈ClN₂O⁺=419.1; found m/z=419.1 (M+1)⁺.

The following compounds can be prepared by this method using analogous starting amides. The BH₃ reduction of amides to amines can also be performed off-resin as is the case for compound 21b4.

wherein R⁶ is hydrogen:

Cpd. # NR⁵R⁶ Mol. Formula Mol. Wt. Obs. Mass (M + 1)⁺ 21a2

C₂₅H₃₁ClN₂O 410.99 411.1 21a3

C₂₄H₃₁ClN₂O 398.98 399.1 21b1

C₂₉H₃₃ClN₂O 461.05 461.1 21b2

C₂₃H₂₉ClN₂O 384.95 385.1 21b3

C₂₇H₂₉ClN₂O 433.0 433.1 21b4

C₂₂H₂₇ClN₂O₂ 386.9 387.1

The following compounds were synthesized using method 18 starting with resin bound N-alkylanilines 21 generated from method 21.

Ret. Time Obs. Mass Cpd. # R⁸ R⁶ Mol. Formula Mol. Wt. (min) (M + 1)⁺ 22a1

CH₂CH₃ C₂₈H₂₉ClN₂O₂ 461.0 4.26 461.1 22a2

CH₂CH₃ C₂₇H₃₃ClN₂O₂ 453.0 4.31 453.1 22a3

CH₂CH₃ C₂₆H₃₃ClN₂O₂ 441.0 4.31 441.1 22b1

CH₂CH₃ C₃₁H₃₃ClN₂O₂ 503.1 4.66 503.1 22b2

CH₂CH₃ C₂₄H₂₉ClN₂O₃ 429.0 3.56 429.1 22b3

CH₂CH₃ C₂₅H₃₁ClN₂O₂ 427.0 4.01 427.1 22b4

CH₂CH₃ C₂₉H₃₁ClN₂O₂ 475.0 4.41 475.1

To a mixture of 0.21 g (0.7 mmol/g) of the sulfonylated resin 19b, 0.19 g (0.725 mmoL, 5 eq) of triphenylphosphine, 0.30 ml (10 eq) of anhydrous methanol in 6 mL of tetrahydrofuran was added a solution of 0.185 g (0.735 mmol, 5 eq.) of 1,1′-(azodicarbonyl)dipiperidine in 2 mL of dichloromethane. The reaction mixture was degassed with nitrogen and shaken overnight with heating at 70° C. The resin was filtered, and washed twice with 5% acetic acid (AcOH) in dichloromethane, each time shaking for 20 minutes. The resin was then washed consecutively with dichloromethane, THF and methanol (3 times each), and finally washed with twice with dichloromethane. The compound was cleaved with 30% trifluoroacetic acid in dichloromethane for 30 min. The product was isolated by preparative thin layer chromatography eluting with 5% methanol in dichloromethane containing 0.5% triethylamine) to give 0.006 g of 23. RP-LC MS: RT=3.16 min, m/z cacld for C₂₁H₂₆ClN₂O₃S⁺=421.14 (M+1)⁺, found m/z=421.1.

To 0.035 g of the resin-bound aniline 17 (0.69 mmol/g) pre-swelled in dichloromethane was added a solution of methychloroformate (5 eq) in dichloromethane. The mixture was agitated overnight and the resin washed sequentially with THF, dichloromethane and methanol. T he product was cleaved from the resin with 30% TFA in dichloromethane to give 4 mg of compound 24a1. RP-LC MS: m/z calcd for C₂₁H₂₄ClN₂O₃ ⁺=387.1; found m/z=387.1 (M+1)⁺.

The following compounds were synthesized using the same method.

Obs. Mass Cpd. # R⁸ Mol. Formula Mol. Wt. (M + 1)⁺ 24a2 Et— C₂₂H₂₅ClN₂O₃ 400.9 400.9 24a3

C₂₇H₂₇ClN₂O₄ 479.0 479.0 24a4 PhCH₂— C₂₇H₂₇ClN₂O₃ 463.0 463.0 24a5 n-Bu— C₂₄H₂₉ClN₂O₃ 429.0 429.1 24b1 Et— C₂₂H₂₅ClN₂O₃ 400.9 402.1 24b2

C₂₇H₂₇ClN₂O₄ 479.0 480.1

To 40 mg (0.62 mmol/g) of a preconditioned mixture of resin bound aldehyde 4a (intermediate from method 5) in 1 mL of N-methylpyrrolidinone was added 2-aminothiophenol (0.025 mL, 0.23 mmol) and 0.007 mL (0.12 mmol) of acetic acid. The mixture was agitated at ambient temperature for 96 hours open to the atmosphere. The resin was filtered and washed with three times with methanol and five times with dichloromethane. T he product was cleaved from the solid support by treatment with 1 mL of 3% TFA in dichloromethane for 20 minutes. The liquid was drained, and the resin was washed three times with dichloromethane. The combined filtrates were concentrated to dryness, and the residue was purified by preparative TLC eluting with 2M NH₃ in methanol/dichloromethane (5:95) to provide 25a as a solid (6 mg): LCMS: m/z calcd for C₂₆H₂₃ClN₂OS⁺(M+1)⁺=447.1, found m/z=447.1.

Compound 25b could also be prepared using similar methodology starting with 1,2-phenylenediamine: LCMS: m/z calcd for C₂₆H₂₃ClN₃O⁺ (M+1)⁺=430.7. found m/z=430.1.

Method 25.1

Analogously to method 25, the imidazole derivative 25c could be prepared from aldehyde 4a as follows:

To a mixture of 60 mg (0.18 mmol) of aldehyde 4a and 0.070 mL of glyoxal (40% in H₂O, 0.48 mmol) cooled to 0° C. was added 1.6 mL (11.2 mmol) of 7N ammonia in methanol solution. The mixture was sealed and stirred at ambient temperature for 68 hours. The solvent was removed in vacuo and the dark residue was purified by preparative TLC eluting with 1% Et₂NH in methanol/dichloromethane (5:95) to provide 49 mg of 25c as a solid: LCMS: m/z calcd for C₂₂H₂₃ClN₃O⁺ (M+1)⁺=380.1; found m/z=380.1.

To a solution of NaOH (1 g) in 10 mL water was added CuSO₄ (0.5 g) and the resulting mixture was stirred for 15 minutes at room temperature. Compound 3a (0.1 g, 2.54 mmol) was added and the mixture was heated at 135° C. for 48 hours. The mixture was neutralized with 6N HCl and poured into a mixture of saturated NaHCO₃/dichloromethane. The mixture was extracted with dichloromethane and the organic layer was dried over sodium sulfate. The solvent was removed in vacuo and the product was isolated by preparative TLC using 10% methanol/dichloromethane as eluent to give 0.03 g of the desired phenol 26a: ES MS: m/z calcd for C₁₉H₂₀ClNO₂ ³⁰=330.1; found m/z=330.1 (M+1)⁺.

Compound 3a (1 g, 2.54 mmol) was mixed with Zn(CN)₂ (0.3 g, 2.56 mmol, 1 eq), Pd₂(dba)₃ (0.116 g, 5 mol %) and dppf (0.17 g, 12 mol %) in 10 mL of DMF. Water (100 μL) was added and the mixture was heated in a sealed tube for 12 hours. Ethyl acetate (200 mL) and 50 mL of water was added and the mixture was reextracted with ethyl acetate (200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The product was purified by silica gel column chromatography using 10% MeOH in dichloromethane as eluent to give 0.76 g of the cyano compound, 27a. ES MS: m/z calcd for C₂₀H₂₀ClN₂O⁺=339.1; found m/z=339.1 (M+1)⁺.

To a suspension of 1.1 of AlCl₃ (4.2 eq) in 20 ml of anhydrous dichloroethane (DCE) cooled to −15° C. was added 1 eq of 2a in 5 ml of DCE followed by 1,1-dichloromethylmethylether (4 eq). The reaction was warmed to room temperature and quenched with by addition of 2.0 g of tartaric acid. The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried and evaporated to give 1.2 g of a mixture of regioisomeric aldehydes 28a in an approximate ratio 1:1:3 as the 10:11:12-isomers.

A solution of 0.5 g of 28a (1 mmol) and hydroxyamine hydrochloride (2 eq) in 5 ml of pyridine was heated under reflux for 30 min and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated to give a solid. Recrystallization from methanol gave 200 mg of oxime 31a. RP-LC MS: calcd for C₂₀H₂₂ClN₂O₂ ⁺=357.1; found=357.1 (M+1)⁺.

A mixture of 500 mg of 31a (1 mmol) in aqueous Ti(III)Cl₃ (5 ml, 8.9% wt in 30% HCl) was stirred overnight under nitrogen. The mixture was poured into saturated sodium carbonate followed by extraction with dichloromethane. The combined organic layers were dried and the solvent evaporated to give a mixture of two products which was chromatographed over silica gel eluting to give 290 mg 4b and 150 mg of 31c: RP-LC MS: calcd for C₂₀H₂₂ClN₂O₂ ⁺=357.1; found=357.1 (M+1)⁺.

A mixture of pyridine (8.5 mL) and concentrated aqueous HCl (10 mL) was heated at 225° C. for 30 minutes and the water was removed by using a Dean-Stark apparatus. To this pyridine.HCl salt, compound 3a (0.1 g, 0.254 mmol) was added and heated at 225° C. for 16 hours. The reaction mixture was cooled to room temperature and carefully quenched by the addition of saturated NaHCO₃ solution (100 mL). The mixture was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over sodium sulfate and the solvent was evaporated in vacuo. The compound was isolated by silica gel column chromatography using 3-10% MeOH in dichloromethane to give 0.05 g of the demethylated product 29a: ES MS: m/z calcd for C₁₈H₁₈BrClNO⁺=380.1; found m/z=380.1 (M+1)⁺.

The following compounds can also be prepared by this method:

Cpd. # R² Analytical data 29b —CN ES MS: calcd for C₁₉H₁₈ClN₂O⁺ = 325.1; found = 325.1 (M + 1)⁺ 29c

ES MS: calcd for C₂₃H₂₂ClN₂O⁺ =377.1; found = 377.1 (M + 1)⁺

To a suspension of 0.116 g (0.25 mmol) of the hydrochloric acid salt of 19b1 and 0.214 g (1.0 mmol) proton sponge in 5 mL of dichloromethane was added 0.12 g (1.13 mmol) of vinyl chloroformate and the mixture was heated overnight at reflux. The intermediate was isolated by silica gel preparative thin layer chromatography eluting with 10% methanol in dichloromethane containing 0.5% triethylamine. The isolated material was dissolved in 2N hydrochloric acid in methanol and heated under reflux overnight. The solvent was removed in vacuo and the resulting solid was redissolved in water. The pH was adjusted to ˜7 with sodium bicarbonate, and the mixture was extracted with ethyl acetate. Concentration and purification by silica gel preparative thin layer chromatography eluting with 5% methanol in dichloromethane containing 0.5% triethylamine gave 2 mg of benzazepine 30a: RP-LC MS: m/z calcd for C₁₉H₂₂ClN₂O₃S⁺=393.1; found m/z=393.1 (M+1)⁺.

A solution of 1.0 g of amide 31c was heated under reflux in 2N HCl for 2 h. The solvent was removed in vacuo and the residue was dissolved in methanol. After addition of 0.50 ml of concentrated sulfuric acid, the solution was heated under reflux overnight. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane and washed with concentrated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated to give 0.9 gram of 32: RP-LC MS: m/z calcd for C₂₁H₂₃ClNO₃ ⁺=372.1; found m/z=372.1 (M+1)⁺.

To 0.15 g (0.381 mmol) the bromo compound 3a dissolved in 2 mL of DMF was treated with 0.1 mL of 2-pyrrolidinone, 0.5 g (5 eq) copper powder and 0.1 g (2 eq) of potassium carbonate. The contents were heated in a sealed tube at 150° C. for 48 hours. The reaction mixture was cooled, passed through a short pad of celite and washed several times with ethyl acetate. The solvent was removed in vacuo and the product was isolated by preparative TLC eluting with 10% methanol in dichloromethane to give 0.037 g of the desired lactam: ES MS: m/z calcd for C₂₃H₂₆ClN₂O₂ ⁺=397.1; found m/z=397.1 (M+1)⁺

The following compounds could be prepared according to the above scheme using methods 4-7 as appropraite, followed by deprotection of the benzazepine nitrogen with trifluoroacetic acid:

Compound Compd # Mol. Formula Calc. MS Found (M + 1)

34a1 C₂₂H₂₇ClN₂O₃S 435 435

34a2 C₂₃H₂₇ClN₂O₂ 399 399

34a3 C₂₆H₂₉ClN₂O 421 422

The acid (0.7 g, 2.02 mmol) was dissolved in 15 mL freshly distilled t-BuOH and 4 mL N-methylpyrrolidinone. It was treated with Hünig's base (0.35 mL, 1 eq) and diphenylphosphoryl azide (DPPA) (0.56 g, 1 eq). The mixture was heated to 90° C. overnight. The solvent was removed in vacuo. The residue was partioned between EtOAc and saturated NaHCO₃. The EtOAc layer was washed with brine and the solvent was removed to give a mixture of compounds. The desired NH-Boc compound was purified by prep TLC, followed by treatment with 30% TFA in dichloromethane to afford the desired aniline product. ¹HNMR (CDCl₃) δ 2.40 (m, 1H) 2.40 (s, 3H) 2.70-3.20 (m, 5H) 3.60 (s, 3H) 4.28 (d, 1H, J=8.4 Hz) 6.28 (s, 1H) 6.68 (d, 2H, J=8.8 Hz) 6.98 (d, 2H, J=8.8 Hz) 7.10 (s, 1H). ¹³CNMR (CDCl₃) δ 35.70 48.50 49.48 57.15 58.12 63.98 114.01 116.46 120.30 130.08 131.77 133.04 134.66 145.43 146.02 153.99. Calcd. Mass for C₁₈H₂₁ClN₂O⁺: 317; found: 317.

The aniline (30 mg, 0.09 mmol) was treated with pyridine (50 mg, 7 eq), MeSO₂Cl (52 mg, 5 eq) and stirred for 3 h. EtOAc was added and the mixture was washed with NaHCO₃ and water. Prep TLC provided the desired product (28 mg). ¹HNMR (CDCl₃) δ 2.38 (s, 3H) 2.42 (m, 1H) 2.60-3.00 (m, 5H) 3.00 (s, 3H) 3.60 (s, 3H) 4.20 (br s,1H) 6.28 (s, 1H) 7.20 (m, 5H).

The final deprotection of O-Me was carried out with BBr₃ according to The final deprotection of O-Me was carried out with BBr₃ according to Org. Synth., Collect. Vol. V, 412 (1973). to give 35a1: ¹HNMR (CDCl₃) δ 2.35 (m, 1H) 2.38 (s, 3H) 2.42 (m, 1H) 2.60-3.00 (m, 5H) 3.10 (s, 3H) 4.20 (d, 1H, J=8.4 Hz) 6.30 (s, 1H). 7.20 (m, 5H). ¹³CNMR (DMSO) δ 34.06 47.50 48.00 57.00 5 61.98 116.20 116.96 120.30 129.08 130.10 133.54 136.20 138.85 144.20 151.99. Calcd. Mass for C₁₈H₂₁ClN₂O₃S⁺:381; found: 381.

The following compound was prepared analogously to the above procedure:

Structure Cmpd # Mol. Formula Calcd Mass Found (M + 1)

35a2 C₂₃H₂₃ClN₂O₃S 443 443

The aldehyde (60 mg, 0.19 mmol) was treated with 1 mL tetrahydrofuran and 0.2 mL MeMgBr (3 M, 3 eq ) at 0° C. for 10 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated in vacuo to give 21 mg of the desired product, 36a¹HNMR (CDCl₃) δ 1.50 (d, 3H, J=6.4 Hz) 2.30 (m, 1H) 2.36 (s, 3H) 2.70-3.10 (m, 5H) 4.20 (m, 1H) 4.80 (m, 1H) 6.20 (d, 1H, J=6.6 Hz) 7.00-7.40 (m, 5H): Calcd. Mass for C₁₉H₂₂ClNO₂ ⁺:332; found: 332.

The compounds of the present invention exhibit D₁/D₅ receptor antagonizing activity, which has been correlated with pharmaceutical activity for treating CNS disorders such as OCD, trichotillomania, metabolic disorders such as obesity, eating disorders such as hyperphagia, and diabetes. This utility is manifested by activity in the following assay.

Assay

Affinity values (Ki) of compounds at human D₁ and D₂ receptors were ascertained using radioligand binding competition assays. Ltk-cells expressing D₁ and D₂ (long variant) receptors were lysed in hypotonic buffer for membrane preparation. Membranes were incubated with various concentrations of test compound and 1 nM [3H] of a compound of formula III and 0.2 nM [3H] Methylspiperone for D₁ and D₂ assays, respectively. Non-specific binding was defined as binding in the presence of 10 micromolar of a compound of formula III for D₁ assays and 10 micromolar butaclamol for D₁ assays. Following incubation to equilibrium (1 hour at room temperature), bound radioligand was separated from free by rapid filtration. Bound radioactivity on the dried filters was quantified by liquid scintillation counting.

Results of the binding assay on compounds of the invention showed Ki (D₁) values of 0.2 to 2835 nM and Ki (D₂) values of 2.1 to >10,000.

Selectivity is determined by dividing Ki for D2 receptor by Ki for D1 receptor.

Compounds with Ki (D₁) values less than 100 nM are designated in the table below as D class compounds.

Compounds with Ki (D₁) values less than 50 nM but greater than 10 nM are designated in the table below as C class compounds.

Compounds of Ki (D₁) values less than 10 nM and a selectivity value greater than 100 are designated in the table below as B class compounds.

Preferred compounds of the invention have Ki (D₁) values less than 5nM and a selectivity value greater than 500 and are designated by the letter A in the table below.

A preferred embodiment of the claimed compounds is example 19b1 with a Ki (D₁) value of 0.45 and D₂:D₁ ratio value of 6642.

TABLE OF D₁ Binding and Selectivity (D₂:D₁ Ratio) D₁ binding and D₂:D₁ Ex. Selectivity  5a14 B  5b46 D  6a6 C  6b1 C  7b7 D  8a3 C  8b11 D 13a2 B 13a6 C 15l C 18a6 A 18b15 C 19a6 B 19b5 A 20a33 C 20b30 A 21a1 A 22a2 C 22b1 C 14t A 19b1 A  5a1 A  7c18 A 24a1 A 24b2 A 20a8 A 29c A 21a2 A 20b5 B  5a50 A 19b31 A  5a38 A 13a7 A 24a2 A 20b6 A 24a3 A 19b32 A 19b23 A 13a12 B 20a7 A 13a21 B 18a1 A 23 A 25c A 27a B 13a24 A 35a1 A 13a20 B 13a19 B 18a4 B 19b24 B 13a14 B 18a8 B 13a16 B 30a B  5c16 A  6c26 A  7c16 A  8c33 B 13d1 C 34a2 B 35a2 B

While the present invention has been described with in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention. 

1. A compound represented by structural formula:

or a pharmaceutically acceptable salt of said compound, isomer or racemic mixture wherein G is hydrogen, halogen, alkyl, alkylthio, nitro, nitrile, hydroxy, alkoxy, alkylsulfinyl, alkylsulfonyl, trifluoromethyl or trifluromethoxy; R¹ is hydrogen, alkyl, allyl, cycloalkyl or cycloalkyl(alkyl); R² is one substituent selected from the group consisting of trifluoromethoxy, aryl, —NO₂, —NR⁵R⁶, —(CH₂)₁₋₆—NR⁵R⁶, —N(R⁶)C((R⁷)(R⁸))C(O)R⁸, —CN, heteroaryl, —C(O)OR⁸, —C(O)NR³R⁴, —C(R⁷)(R⁸)NR⁵R^(6, —C(R) ⁷)═NOR⁴ and —C(R⁷)(R⁸)OR⁶; R³ and R⁴ are aryl, aralkyl, alkenyl, heterocyclyl, heteroaryl, cycloalkyl, cycloalkylalkyl, heteroaralkyl, heterocyclylalkyl, alkyl or hydrogen, or R³, R⁴ and the N to which they are attached can be joined together to form a ring selected from the group consisting of azetidine, azepane, indane, pyrrolidine, piperidine, piperazine, morpholine and

wherein said ring is unsubstituted or optionally substituted with one to four R¹⁰ moieties; R⁵ is hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heteroaralkyl, —C(O)NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R⁸, —C(O)R⁸, —C(O)OR⁸ or —R⁹; R⁶ is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaralkyl, heterocyclylalkyl, heterocyclyl or heteroaryl, or R⁵, R⁶ and the N to which they are attached can be joined together to form a ring selected from the group consisting of azetidine, azepane, indane, pyrrolidine, piperidine, piperazine, morpholine and

wherein said ring is unsubstituted or optionally substituted with one to four R¹⁰ moieties; R⁷ is hydrogen, alkyl, aryl or aralkyl; R⁸ is hydrogen, aryl, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heteroaryl; R⁹ is alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl or alkoxyaralkyl; R¹⁰ is 1 to 4 substituents which can be the same or different, each R¹⁰ being independently selected from the group consisting of alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, alkoxycarbonylalkylenyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, trifluoromethyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁C(O)N—, Y₁Y₂NC(O)— and Y₁Y₂NS(O)₂—, wherein Y₁ and Y₂ may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl or two R¹⁰ groups on adjacent carbons can be joined together to form a methylenedioxy or ethylenedioxy group; and R¹¹ is hydrogen or alkyl; wherein each of said alkyl, allyl, alkylenyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, alkoxyalkyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, hydroxyalkyl, cycloalkylalkyl, heterocyclyl and cycloalkyl is unsubstituted or optionally substituted with one to four R¹⁰ moieties, where two adjacent R¹⁰ groups can be joined together to form a methylenedioxy or ethylenedioxy group.
 2. The compound according to claim 1 wherein R¹¹ is hydrogen.
 3. The compound according to claim 1 wherein G is halogen.
 4. The compound according to claim 1 wherein G is chloro.
 5. The compound according to claim 1 wherein R¹ is hydrogen or alkyl.
 6. The compound according to claim 1 wherein R¹ is hydrogen or methyl.
 7. The compound according to claim 1 wherein G is halogen, R¹ is alkyl and R¹¹ is hydrogen.
 8. The compound according to claim 7 wherein G is chloro, R¹ is methyl.
 9. The compound according to claim 1 wherein R² is —CH₂—NR⁵R⁶; R⁵ is hydrogen; and R⁶ is


10. The according to claim 1 wherein R² is —CH₂—NR⁵R⁶; R⁵ is C(O)CH₃; and R⁶ is


11. The compound according to claim 1 wherein R² is —CH₂—NR⁵R⁶; R⁵ is benzyl; and R⁶ is


12. The compound according to claim 1 wherein R² is —CH₂—NR⁵R⁶; R⁵ is —S(O)₂-methyl; and R⁶ is


13. The compound according to claim 1 wherein R² is —CH₂—NR⁵R⁶; R⁵ is —S(O)₂-methyl; and R⁶ is


14. The compound according to claim 1 wherein R² is —CH₂—NR⁵R⁶; R⁵ is —C(O)NH-ethyl; and R⁶ is


15. The compound according to claim 1 wherein R² is —CH₂—NR⁵R⁶; R⁵ is —C(O)NH-isopropyl; and R⁶is


16. The compound according to claim 1 wherein R² is selected from the group consisting of


17. The compound according to claim 1 wherein R² is selected from the group consisting of:


18. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 19. A method of treating an eating disorder comprising administering to a patient a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt of said compound, to a patient in need of such treatment.
 20. A method of treating an eating disorder comprising administering to a patient a therapeutically effective amount of at least one compound of claim 18, or a pharmaceutically acceptable salt of said compound, to a patient in need of such treatment.
 21. The method of claim 19 wherein said eating disorder is hyperphagia.
 22. The method of claim 20 wherein said eating disorder is hyperphagia.
 23. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt of said compound, in combination with at least one pharmaceutically acceptable carrier.
 24. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 18, or a pharmaceutically acceptable salt of said compound, in combination with at least one pharmaceutically acceptable carrier.
 25. A process for making a pharmaceutical composition comprising combining at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
 26. A process for making a pharmaceutical composition comprising combining at least one compound of claim 18, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 